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Katsanis, Nicholas

Positions:

Jean and George W. Brumley, Jr., M.D. Professor of Developmental Biology

Cell Biology
School of Medicine

Professor of Cell Biology

Cell Biology
School of Medicine

Professor of Pediatrics

Pediatrics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1997

Ph.D. — Imperial College London (Uk)

News:

Grants:

The Role of Basal Bodies in Wnt Signaling

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2007
End Date
July 31, 2020

NINDS Research Education Programs for Residents and Fellows in Neurosurgery

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
March 01, 2009
End Date
June 30, 2019

Functional and Phenotypic Characterization of a New FSGS Gene

Administered By
Pediatrics, Nephrology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 24, 2014
End Date
May 31, 2019

Genetic and Functional Studies of Human Ciliary Syndromes

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2005
End Date
February 28, 2019

Molecular Genetics of BBS

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2002
End Date
May 31, 2018

Center for Undiagnosed Pediatric and Urogenital Disorders

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2012
End Date
August 31, 2017

Genetic and Molecular Analysis of Congenital Heart Disease

Administered By
Institutes and Centers
AwardedBy
University of Chicago
Role
Principal Investigator
Start Date
August 01, 2015
End Date
July 31, 2017

Functional dissection of GnRH defects and networks

Administered By
Institutes and Centers
AwardedBy
Massachusetts General Hospital
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Development of Therapeutics for Ciliopathies

Administered By
Institutes and Centers
AwardedBy
GlaxoSmithKline
Role
Principal Investigator
Start Date
March 09, 2015
End Date
June 30, 2017

Gene Discovery in Autosomal Dominant Focal Segmental Glomerulosclerosis

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 18, 2012
End Date
June 30, 2017

Gene-Environment Interactions for Cortical Development and Schizophrenia

Administered By
Institutes and Centers
AwardedBy
Johns Hopkins University
Role
Principal Investigator
Start Date
July 12, 2011
End Date
June 30, 2017

Genomic Architecture of Common Disease in Diverse Populations

Administered By
Institutes and Centers
AwardedBy
Baylor College of Medicine
Role
Principal Investigator
Start Date
January 14, 2016
End Date
November 30, 2016

Genetics of Fuchs Corneal Dystrophy

Administered By
Institutes and Centers
AwardedBy
Johns Hopkins University
Role
Principal Investigator
Start Date
September 01, 2010
End Date
August 31, 2016

Analysis of KCTD13 as the primary candidate for the 16p11.2 CNV

Administered By
Institutes and Centers
AwardedBy
Brain and Behavior Research Foundation
Role
Principal Investigator
Start Date
January 15, 2014
End Date
January 14, 2016

Dissecting reciprocal CNVs associated with autism

Administered By
Institutes and Centers
AwardedBy
Brain and Behavior Research Foundation
Role
Principal Investigator
Start Date
January 15, 2014
End Date
January 14, 2016

Genetic and Functional Interaction between the proteasome and the Primary Cilium

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2012
End Date
August 31, 2015

Multidisciplinary Neonatal Training Grant

Administered By
Pediatrics, Neonatology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
April 01, 2010
End Date
June 30, 2015

Genetic and Functional Studies of Human Ciliary Syndromes

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2005
End Date
January 31, 2011

Novel Wnt Effectors in Renal Cystic Disease

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 06, 2007
End Date
July 05, 2010
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Publications:

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Authors
Küry, S; Besnard, T; Ebstein, F; Khan, TN; Gambin, T; Douglas, J; Bacino, CA; Sanders, SJ; Lehmann, A; Latypova, X; Khan, K; Pacault, M; Sacharow, S; Glaser, K; Bieth, E; Perrin-Sabourin, L; Jacquemont, M-L; Cho, MT; Roeder, E; Denommé-Pichon, A-S; Monaghan, KG; Yuan, B; Xia, F; Simon, S; Bonneau, D; Parent, P; Gilbert-Dussardier, B; Odent, S; Toutain, A; Pasquier, L; Barbouth, D; Shaw, CA; Patel, A; Smith, JL; Bi, W; Schmitt, S; Deb, W; Nizon, M; Mercier, S; Vincent, M; Rooryck, C; Malan, V et al.
MLA Citation
Küry, S, Besnard, T, Ebstein, F, Khan, TN, Gambin, T, Douglas, J, Bacino, CA, Sanders, SJ, Lehmann, A, Latypova, X, Khan, K, Pacault, M, Sacharow, S, Glaser, K, Bieth, E, Perrin-Sabourin, L, Jacquemont, M-L, Cho, MT, Roeder, E, Denommé-Pichon, A-S, Monaghan, KG, Yuan, B, Xia, F, Simon, S, Bonneau, D, Parent, P, Gilbert-Dussardier, B, Odent, S, Toutain, A, Pasquier, L, Barbouth, D, Shaw, CA, Patel, A, Smith, JL, Bi, W, Schmitt, S, Deb, W, Nizon, M, Mercier, S, Vincent, M, Rooryck, C, and Malan, V et al. "De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder." American journal of human genetics 100.2 (February 2017): 352-363.
PMID
28132691
Source
epmc
Published In
The American Journal of Human Genetics
Volume
100
Issue
2
Publish Date
2017
Start Page
352
End Page
363
DOI
10.1016/j.ajhg.2017.01.003

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Authors
Shaw, ND; Brand, H; Kupchinsky, ZA; Bengani, H; Plummer, L; Jones, TI; Erdin, S; Williamson, KA; Rainger, J; Stortchevoi, A; Samocha, K; Currall, BB; Dunican, DS; Collins, RL; Willer, JR; Lek, A; Lek, M; Nassan, M; Pereira, S; Kammin, T; Lucente, D; Silva, A; Seabra, CM; Chiang, C; An, Y; Ansari, M; Rainger, JK; Joss, S; Smith, JC; Lippincott, MF; Singh, SS; Patel, N; Jing, JW; Law, JR; Ferraro, N; Verloes, A; Rauch, A; Steindl, K; Zweier, M; Scheer, I; Sato, D; Okamoto, N; Jacobsen, C et al.
MLA Citation
Shaw, ND, Brand, H, Kupchinsky, ZA, Bengani, H, Plummer, L, Jones, TI, Erdin, S, Williamson, KA, Rainger, J, Stortchevoi, A, Samocha, K, Currall, BB, Dunican, DS, Collins, RL, Willer, JR, Lek, A, Lek, M, Nassan, M, Pereira, S, Kammin, T, Lucente, D, Silva, A, Seabra, CM, Chiang, C, An, Y, Ansari, M, Rainger, JK, Joss, S, Smith, JC, Lippincott, MF, Singh, SS, Patel, N, Jing, JW, Law, JR, Ferraro, N, Verloes, A, Rauch, A, Steindl, K, Zweier, M, Scheer, I, Sato, D, Okamoto, N, and Jacobsen, C et al. "SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome." Nature genetics (January 9, 2017).
PMID
28067909
Source
epmc
Published In
Nature Genetics
Publish Date
2017
DOI
10.1038/ng.3743

Molecular Genetic Testing and the Future of Clinical Genomics

© 2017 Elsevier Inc. All rights reserved.Central to the precision medicine trend is the ability to test for genomic variation in a given patient and use the variation to offer diagnoses and precision treatment. In most cases, tests for variation involve clinical molecular genetic tests. Genetic tests for germline variation include tests for macro-scale molecular changes, such as cytogenetic differences, and micro-scale variation of differences at the nucleotide level. The recent shift to genome sequence analysis brings with it challenges for interpreting genetic variation, particularly rare differences, that all humans carry.

Authors
Katsanis, SH; Katsanis, N
MLA Citation
Katsanis, SH, and Katsanis, N. "Molecular Genetic Testing and the Future of Clinical Genomics." Genomic and Precision Medicine: Foundations, Translation, and Implementation: Third Edition. December 15, 2016. 263-282.
Source
scopus
Publish Date
2016
Start Page
263
End Page
282
DOI
10.1016/B978-0-12-800681-8.00018-9

The continuum of causality in human genetic disorders.

Studies of human genetic disorders have traditionally followed a reductionist paradigm. Traits are defined as Mendelian or complex based on family pedigree and population data, whereas alleles are deemed rare, common, benign, or deleterious based on their population frequencies. The availability of exome and genome data, as well as gene and allele discovery for various conditions, is beginning to challenge classic definitions of genetic causality. Here, I discuss recent advances in our understanding of the overlap between rare and complex diseases and the context-dependent effect of both rare and common alleles that underscores the need for revising the traditional categorizations of genetic traits.

Authors
Katsanis, N
MLA Citation
Katsanis, N. "The continuum of causality in human genetic disorders." Genome biology 17.1 (November 17, 2016): 233-.
PMID
27855690
Source
epmc
Published In
Genome Biology: biology for the post-genomic era
Volume
17
Issue
1
Publish Date
2016
Start Page
233

Gene expression elucidates functional impact of polygenic risk for schizophrenia.

Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

Authors
Fromer, M; Roussos, P; Sieberts, SK; Johnson, JS; Kavanagh, DH; Perumal, TM; Ruderfer, DM; Oh, EC; Topol, A; Shah, HR; Klei, LL; Kramer, R; Pinto, D; Gümüş, ZH; Cicek, AE; Dang, KK; Browne, A; Lu, C; Xie, L; Readhead, B; Stahl, EA; Xiao, J; Parvizi, M; Hamamsy, T; Fullard, JF; Wang, Y-C; Mahajan, MC; Derry, JMJ; Dudley, JT; Hemby, SE; Logsdon, BA; Talbot, K; Raj, T; Bennett, DA; De Jager, PL; Zhu, J; Zhang, B; Sullivan, PF; Chess, A; Purcell, SM; Shinobu, LA; Mangravite, LM; Toyoshiba, H et al.
MLA Citation
Fromer, M, Roussos, P, Sieberts, SK, Johnson, JS, Kavanagh, DH, Perumal, TM, Ruderfer, DM, Oh, EC, Topol, A, Shah, HR, Klei, LL, Kramer, R, Pinto, D, Gümüş, ZH, Cicek, AE, Dang, KK, Browne, A, Lu, C, Xie, L, Readhead, B, Stahl, EA, Xiao, J, Parvizi, M, Hamamsy, T, Fullard, JF, Wang, Y-C, Mahajan, MC, Derry, JMJ, Dudley, JT, Hemby, SE, Logsdon, BA, Talbot, K, Raj, T, Bennett, DA, De Jager, PL, Zhu, J, Zhang, B, Sullivan, PF, Chess, A, Purcell, SM, Shinobu, LA, Mangravite, LM, and Toyoshiba, H et al. "Gene expression elucidates functional impact of polygenic risk for schizophrenia." Nature neuroscience 19.11 (November 2016): 1442-1453.
PMID
27668389
Source
epmc
Published In
Nature Neuroscience
Volume
19
Issue
11
Publish Date
2016
Start Page
1442
End Page
1453
DOI
10.1038/nn.4399

DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes.

Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.

Authors
Dougherty, GW; Loges, NT; Klinkenbusch, JA; Olbrich, H; Pennekamp, P; Menchen, T; Raidt, J; Wallmeier, J; Werner, C; Westermann, C; Ruckert, C; Mirra, V; Hjeij, R; Memari, Y; Durbin, R; Kolb-Kokocinski, A; Praveen, K; Kashef, MA; Kashef, S; Eghtedari, F; Häffner, K; Valmari, P; Baktai, G; Aviram, M; Bentur, L; Amirav, I; Davis, EE; Katsanis, N; Brueckner, M; Shaposhnykov, A; Pigino, G; Dworniczak, B; Omran, H
MLA Citation
Dougherty, GW, Loges, NT, Klinkenbusch, JA, Olbrich, H, Pennekamp, P, Menchen, T, Raidt, J, Wallmeier, J, Werner, C, Westermann, C, Ruckert, C, Mirra, V, Hjeij, R, Memari, Y, Durbin, R, Kolb-Kokocinski, A, Praveen, K, Kashef, MA, Kashef, S, Eghtedari, F, Häffner, K, Valmari, P, Baktai, G, Aviram, M, Bentur, L, Amirav, I, Davis, EE, Katsanis, N, Brueckner, M, Shaposhnykov, A, Pigino, G, Dworniczak, B, and Omran, H. "DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes." American journal of respiratory cell and molecular biology 55.2 (August 2016): 213-224.
PMID
26909801
Source
epmc
Published In
American journal of respiratory cell and molecular biology
Volume
55
Issue
2
Publish Date
2016
Start Page
213
End Page
224
DOI
10.1165/rcmb.2015-0353oc

Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.

Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

Authors
Lindstrand, A; Frangakis, S; Carvalho, CMB; Richardson, EB; McFadden, KA; Willer, JR; Pehlivan, D; Liu, P; Pediaditakis, IL; Sabo, A; Lewis, RA; Banin, E; Lupski, JR; Davis, EE; Katsanis, N
MLA Citation
Lindstrand, A, Frangakis, S, Carvalho, CMB, Richardson, EB, McFadden, KA, Willer, JR, Pehlivan, D, Liu, P, Pediaditakis, IL, Sabo, A, Lewis, RA, Banin, E, Lupski, JR, Davis, EE, and Katsanis, N. "Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome." American journal of human genetics 99.2 (August 2016): 318-336.
PMID
27486776
Source
epmc
Published In
The American Journal of Human Genetics
Volume
99
Issue
2
Publish Date
2016
Start Page
318
End Page
336
DOI
10.1016/j.ajhg.2015.04.023

The Genetic Basis of Hydrocephalus.

Studies of syndromic hydrocephalus have led to the identification of >100 causative genes. Even though this work has illuminated numerous pathways associated with hydrocephalus, it has also highlighted the fact that the genetics underlying this phenotype are more complex than anticipated originally. Mendelian forms of hydrocephalus account for a small fraction of the genetic burden, with clear evidence of background-dependent effects of alleles on penetrance and expressivity of driver mutations in key developmental and homeostatic pathways. Here, we synthesize the currently implicated genes and inheritance paradigms underlying hydrocephalus, grouping causal loci into functional modules that affect discrete, albeit partially overlapping, cellular processes. These in turn have the potential to both inform pathomechanism and assist in the rational molecular classification of a clinically heterogeneous phenotype. Finally, we discuss conceptual methods that can lead to enhanced gene identification and dissection of disease basis, knowledge that will potentially form a foundation for the design of future therapeutics.

Authors
Kousi, M; Katsanis, N
MLA Citation
Kousi, M, and Katsanis, N. "The Genetic Basis of Hydrocephalus." Annual review of neuroscience 39 (July 2016): 409-435.
PMID
27145913
Source
epmc
Published In
Annual Review of Neuroscience
Volume
39
Publish Date
2016
Start Page
409
End Page
435
DOI
10.1146/annurev-neuro-070815-014023

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

Authors
Bolar, NA; Golzio, C; Živná, M; Hayot, G; Van Hemelrijk, C; Schepers, D; Vandeweyer, G; Hoischen, A; Huyghe, JR; Raes, A; Matthys, E; Sys, E; Azou, M; Gubler, M-C; Praet, M; Van Camp, G; McFadden, K; Pediaditakis, I; Přistoupilová, A; Hodaňová, K; Vyleťal, P; Hartmannová, H; Stránecký, V; Hůlková, H; Barešová, V; Jedličková, I; Sovová, J; Hnízda, A; Kidd, K; Bleyer, AJ; Spong, RS; Vande Walle, J; Mortier, G; Brunner, H; Van Laer, L; Kmoch, S; Katsanis, N; Loeys, BL
MLA Citation
Bolar, NA, Golzio, C, Živná, M, Hayot, G, Van Hemelrijk, C, Schepers, D, Vandeweyer, G, Hoischen, A, Huyghe, JR, Raes, A, Matthys, E, Sys, E, Azou, M, Gubler, M-C, Praet, M, Van Camp, G, McFadden, K, Pediaditakis, I, Přistoupilová, A, Hodaňová, K, Vyleťal, P, Hartmannová, H, Stránecký, V, Hůlková, H, Barešová, V, Jedličková, I, Sovová, J, Hnízda, A, Kidd, K, Bleyer, AJ, Spong, RS, Vande Walle, J, Mortier, G, Brunner, H, Van Laer, L, Kmoch, S, Katsanis, N, and Loeys, BL. "Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia." American journal of human genetics 99.1 (July 2016): 174-187.
PMID
27392076
Source
epmc
Published In
The American Journal of Human Genetics
Volume
99
Issue
1
Publish Date
2016
Start Page
174
End Page
187
DOI
10.1016/j.ajhg.2016.05.028

The potential of DISC1 protein as a therapeutic target for mental illness.

Authors
Sawa, A; Ishizuka, K; Katsanis, N
MLA Citation
Sawa, A, Ishizuka, K, and Katsanis, N. "The potential of DISC1 protein as a therapeutic target for mental illness." Expert opinion on therapeutic targets 20.6 (June 2016): 641-643.
PMID
26810812
Source
epmc
Published In
Expert Opinion on Therapeutic Targets
Volume
20
Issue
6
Publish Date
2016
Start Page
641
End Page
643
DOI
10.1517/14728222.2016.1146694

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.

Authors
Boldt, K; van Reeuwijk, J; Lu, Q; Koutroumpas, K; Nguyen, T-MT; Texier, Y; van Beersum, SEC; Horn, N; Willer, JR; Mans, DA; Dougherty, G; Lamers, IJC; Coene, KLM; Arts, HH; Betts, MJ; Beyer, T; Bolat, E; Gloeckner, CJ; Haidari, K; Hetterschijt, L; Iaconis, D; Jenkins, D; Klose, F; Knapp, B; Latour, B; Letteboer, SJF; Marcelis, CL; Mitic, D; Morleo, M; Oud, MM; Riemersma, M; Rix, S; Terhal, PA; Toedt, G; van Dam, TJP; de Vrieze, E; Wissinger, Y; Wu, KM; Apic, G; Beales, PL; Blacque, OE et al.
MLA Citation
Boldt, K, van Reeuwijk, J, Lu, Q, Koutroumpas, K, Nguyen, T-MT, Texier, Y, van Beersum, SEC, Horn, N, Willer, JR, Mans, DA, Dougherty, G, Lamers, IJC, Coene, KLM, Arts, HH, Betts, MJ, Beyer, T, Bolat, E, Gloeckner, CJ, Haidari, K, Hetterschijt, L, Iaconis, D, Jenkins, D, Klose, F, Knapp, B, Latour, B, Letteboer, SJF, Marcelis, CL, Mitic, D, Morleo, M, Oud, MM, Riemersma, M, Rix, S, Terhal, PA, Toedt, G, van Dam, TJP, de Vrieze, E, Wissinger, Y, Wu, KM, Apic, G, Beales, PL, and Blacque, OE et al. "An organelle-specific protein landscape identifies novel diseases and molecular mechanisms." Nature communications 7 (May 13, 2016): 11491-.
PMID
27173435
Source
epmc
Published In
Nature Communications
Volume
7
Publish Date
2016
Start Page
11491
DOI
10.1038/ncomms11491

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network.

Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers. To identify novel ODA loci, we conducted targeted high-throughput sequencing of 407 candidate genes in an initial cohort of 22 sporadic ODA patients. Patched 1 (PTCH1), an inhibitor of sonic hedgehog (SHH) signaling, harbored an enrichment of rare heterozygous variants in comparison to either controls, or to the other candidate genes (four missense and one frameshift); targeted resequencing of PTCH1 in a second cohort of 48 ODA patients identified two additional rare nonsynonymous changes. Using multiple transient models and a CRISPR/Cas9-generated mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish for which in vivo complementation assays using these models showed that all six patient missense mutations affect SHH signaling. Finally, through transcriptomic and ChIP analyses, we show that SOX2 binds to an intronic domain of the PTCH1 locus to regulate PTCH1 expression, findings that were validated both in vitro and in vivo. Together, these results demonstrate that PTCH1 mutations contribute to as much as 10% of ODA, identify the SHH signaling pathway as a novel effector of SOX2 activity during human ocular development, and indicate that ODA is likely the result of overactive SHH signaling in humans harboring mutations in either PTCH1 or SOX2.

Authors
Chassaing, N; Davis, EE; McKnight, KL; Niederriter, AR; Causse, A; David, V; Desmaison, A; Lamarre, S; Vincent-Delorme, C; Pasquier, L; Coubes, C; Lacombe, D; Rossi, M; Dufier, J-L; Dollfus, H; Kaplan, J; Katsanis, N; Etchevers, HC; Faguer, S; Calvas, P
MLA Citation
Chassaing, N, Davis, EE, McKnight, KL, Niederriter, AR, Causse, A, David, V, Desmaison, A, Lamarre, S, Vincent-Delorme, C, Pasquier, L, Coubes, C, Lacombe, D, Rossi, M, Dufier, J-L, Dollfus, H, Kaplan, J, Katsanis, N, Etchevers, HC, Faguer, S, and Calvas, P. "Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network." Genome research 26.4 (April 2016): 474-485.
PMID
26893459
Source
epmc
Published In
Genome research
Volume
26
Issue
4
Publish Date
2016
Start Page
474
End Page
485
DOI
10.1101/gr.196048.115

Mitochondrial Copy Number as a Biomarker for Autism?

Authors
Golzio, C; Katsanis, N
MLA Citation
Golzio, C, and Katsanis, N. "Mitochondrial Copy Number as a Biomarker for Autism?." Pediatrics 137.4 (April 2016).
PMID
27033113
Source
epmc
Published In
Pediatrics
Volume
137
Issue
4
Publish Date
2016
DOI
10.1542/peds.2016-0049

Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy.

Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype.In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity.Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum.We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.

Authors
Liu, YP; Bosch, DGM; Siemiatkowska, AM; Rendtorff, ND; Boonstra, FN; Möller, C; Tranebjærg, L; Katsanis, N; Cremers, FPM
MLA Citation
Liu, YP, Bosch, DGM, Siemiatkowska, AM, Rendtorff, ND, Boonstra, FN, Möller, C, Tranebjærg, L, Katsanis, N, and Cremers, FPM. "Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy." Ophthalmic genetics (March 30, 2016): 1-6.
PMID
27029556
Source
epmc
Published In
Ophthalmic Genetics (Informa)
Publish Date
2016
Start Page
1
End Page
6

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Authors
Fritsche, LG; Igl, W; Bailey, JNC; Grassmann, F; Sengupta, S; Bragg-Gresham, JL; Burdon, KP; Hebbring, SJ; Wen, C; Gorski, M; Kim, IK; Cho, D; Zack, D; Souied, E; Scholl, HPN; Bala, E; Lee, KE; Hunter, DJ; Sardell, RJ; Mitchell, P; Merriam, JE; Cipriani, V; Hoffman, JD; Schick, T; Lechanteur, YTE; Guymer, RH; Johnson, MP; Jiang, Y; Stanton, CM; Buitendijk, GHS; Zhan, X; Kwong, AM; Boleda, A; Brooks, M; Gieser, L; Ratnapriya, R; Branham, KE; Foerster, JR; Heckenlively, JR; Othman, MI; Vote, BJ et al.
MLA Citation
Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, and Vote, BJ et al. "A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants." Nature genetics 48.2 (February 2016): 134-143.
PMID
26691988
Source
epmc
Published In
Nature Genetics
Volume
48
Issue
2
Publish Date
2016
Start Page
134
End Page
143
DOI
10.1038/ng.3448

Newborn screening and the era of medical genomics.

Across the span of the last 75+ years, technological and conceptual advances in genetics have found rapid implementation at the beginning of human life. From karyotype testing, to molecular cytogenetics, to gene panel testing, and now to whole exome and whole genome sequencing, each iterative expansion of our capability to acquire genetic data on the next generation has been implemented quickly in the clinical setting. In tandem, our continuously expanding ability to acquire large volumes of genetic data has generated its own challenges in terms of interpretation, clinical utility of the information, and concerns over privacy and discrimination; for the first time, we are faced with the possibility of having complete access to our genetic data from birth, if not shortly after conception. Here, we discuss the evolution of the field toward this new reality and we consider the potentially far-reaching consequences and, at present, an unclear path toward developing best practices for implementation.

Authors
Francescatto, L; Katsanis, N
MLA Citation
Francescatto, L, and Katsanis, N. "Newborn screening and the era of medical genomics." Seminars in perinatology 39.8 (December 2015): 617-622. (Review)
PMID
26499764
Source
epmc
Published In
Seminars in Perinatology
Volume
39
Issue
8
Publish Date
2015
Start Page
617
End Page
622
DOI
10.1053/j.semperi.2015.09.010

A human laterality disorder caused by a homozygous deleterious mutation in MMP21.

Laterality in the vertebrate embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid across the embryonic node. Defects in these processes cause heterotaxy, the abnormal formation and arrangement of visceral organs that can range from complete inversion of symmetry to the selective misarrangement of organs. However, our understanding of the genetic causality for laterality defects in human beings remains relatively limited.We performed whole exome sequencing in a consanguineous family with heterotaxia. To interrogate the pathogenic potential of the discovered variant, we used an in vivo system in which the potential of the candidate gene to induce L-R asymmetry was tested by transient suppression and CRISPR/Cas9-induced deletions. We also used in vitro assays to test a possible link between our exome-derived candidate and Notch signaling.We identified a homozygous 2 bp deletion in MMP21, encoding matrix metalloproteinase-21, as the sole coding mutation that segregated with the phenotype. Transient suppression or CRISPR/Cas9-mediated deletion of mmp21 in zebrafish embryos induced cardiac looping defects, with concomitant disruption of laterality markers in the lateral plate mesoderm and disrupted notch signalling in vitro and in vivo.Our data implicate loss of MMP21 as a cause of heterotaxy in humans with concomitant defects in Notch signaling. In support of this finding, a homozygous missense mutation in MMP21 was identified previously in mice with N-Ethyl-N-Nitrosourea (ENU)-induced heterotaxy. Taken together, these observations suggest a role of matrix metalloproteinases in the establishment of asymmetric organ development, likely through the regulation of morphogenetic signals.

Authors
Perles, Z; Moon, S; Ta-Shma, A; Yaacov, B; Francescatto, L; Edvardson, S; Rein, AJJT; Elpeleg, O; Katsanis, N
MLA Citation
Perles, Z, Moon, S, Ta-Shma, A, Yaacov, B, Francescatto, L, Edvardson, S, Rein, AJJT, Elpeleg, O, and Katsanis, N. "A human laterality disorder caused by a homozygous deleterious mutation in MMP21." Journal of medical genetics 52.12 (December 2015): 840-847.
PMID
26429889
Source
epmc
Published In
Journal of medical genetics
Volume
52
Issue
12
Publish Date
2015
Start Page
840
End Page
847
DOI
10.1136/jmedgenet-2015-103336

Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

Authors
Isrie, M; Breuss, M; Tian, G; Hansen, AH; Cristofoli, F; Morandell, J; Kupchinsky, ZA; Sifrim, A; Rodriguez-Rodriguez, CM; Dapena, EP; Doonanco, K; Leonard, N; Tinsa, F; Moortgat, S; Ulucan, H; Koparir, E; Karaca, E; Katsanis, N; Marton, V; Vermeesch, JR; Davis, EE; Cowan, NJ; Keays, DA; Van Esch, H
MLA Citation
Isrie, M, Breuss, M, Tian, G, Hansen, AH, Cristofoli, F, Morandell, J, Kupchinsky, ZA, Sifrim, A, Rodriguez-Rodriguez, CM, Dapena, EP, Doonanco, K, Leonard, N, Tinsa, F, Moortgat, S, Ulucan, H, Koparir, E, Karaca, E, Katsanis, N, Marton, V, Vermeesch, JR, Davis, EE, Cowan, NJ, Keays, DA, and Van Esch, H. "Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type." American journal of human genetics 97.6 (December 2015): 790-800.
PMID
26637975
Source
epmc
Published In
The American Journal of Human Genetics
Volume
97
Issue
6
Publish Date
2015
Start Page
790
End Page
800
DOI
10.1016/j.ajhg.2015.10.014

De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

Authors
Burrage, LC; Charng, W-L; Eldomery, MK; Willer, JR; Davis, EE; Lugtenberg, D; Zhu, W; Leduc, MS; Akdemir, ZC; Azamian, M; Zapata, G; Hernandez, PP; Schoots, J; de Munnik, SA; Roepman, R; Pearring, JN; Jhangiani, S; Katsanis, N; Vissers, LELM; Brunner, HG; Beaudet, AL; Rosenfeld, JA; Muzny, DM; Gibbs, RA; Eng, CM; Xia, F; Lalani, SR; Lupski, JR; Bongers, EMHF; Yang, Y
MLA Citation
Burrage, LC, Charng, W-L, Eldomery, MK, Willer, JR, Davis, EE, Lugtenberg, D, Zhu, W, Leduc, MS, Akdemir, ZC, Azamian, M, Zapata, G, Hernandez, PP, Schoots, J, de Munnik, SA, Roepman, R, Pearring, JN, Jhangiani, S, Katsanis, N, Vissers, LELM, Brunner, HG, Beaudet, AL, Rosenfeld, JA, Muzny, DM, Gibbs, RA, Eng, CM, Xia, F, Lalani, SR, Lupski, JR, Bongers, EMHF, and Yang, Y. "De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome." American journal of human genetics 97.6 (December 2015): 904-913.
PMID
26637980
Source
epmc
Published In
The American Journal of Human Genetics
Volume
97
Issue
6
Publish Date
2015
Start Page
904
End Page
913
DOI
10.1016/j.ajhg.2015.11.006

TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations.

We describe an X-linked genetic syndrome associated with mutations in TAF1 and manifesting with global developmental delay, intellectual disability (ID), characteristic facial dysmorphology, generalized hypotonia, and variable neurologic features, all in male individuals. Simultaneous studies using diverse strategies led to the identification of nine families with overlapping clinical presentations and affected by de novo or maternally inherited single-nucleotide changes. Two additional families harboring large duplications involving TAF1 were also found to share phenotypic overlap with the probands harboring single-nucleotide changes, but they also demonstrated a severe neurodegeneration phenotype. Functional analysis with RNA-seq for one of the families suggested that the phenotype is associated with downregulation of a set of genes notably enriched with genes regulated by E-box proteins. In addition, knockdown and mutant studies of this gene in zebrafish have shown a quantifiable, albeit small, effect on a neuronal phenotype. Our results suggest that mutations in TAF1 play a critical role in the development of this X-linked ID syndrome.

Authors
O'Rawe, JA; Wu, Y; Dörfel, MJ; Rope, AF; Au, PYB; Parboosingh, JS; Moon, S; Kousi, M; Kosma, K; Smith, CS; Tzetis, M; Schuette, JL; Hufnagel, RB; Prada, CE; Martinez, F; Orellana, C; Crain, J; Caro-Llopis, A; Oltra, S; Monfort, S; Jiménez-Barrón, LT; Swensen, J; Ellingwood, S; Smith, R; Fang, H; Ospina, S; Stegmann, S; Den Hollander, N; Mittelman, D; Highnam, G; Robison, R; Yang, E; Faivre, L; Roubertie, A; Rivière, J-B; Monaghan, KG; Wang, K; Davis, EE; Katsanis, N; Kalscheuer, VM; Wang, EH et al.
MLA Citation
O'Rawe, JA, Wu, Y, Dörfel, MJ, Rope, AF, Au, PYB, Parboosingh, JS, Moon, S, Kousi, M, Kosma, K, Smith, CS, Tzetis, M, Schuette, JL, Hufnagel, RB, Prada, CE, Martinez, F, Orellana, C, Crain, J, Caro-Llopis, A, Oltra, S, Monfort, S, Jiménez-Barrón, LT, Swensen, J, Ellingwood, S, Smith, R, Fang, H, Ospina, S, Stegmann, S, Den Hollander, N, Mittelman, D, Highnam, G, Robison, R, Yang, E, Faivre, L, Roubertie, A, Rivière, J-B, Monaghan, KG, Wang, K, Davis, EE, Katsanis, N, Kalscheuer, VM, and Wang, EH et al. "TAF1 Variants Are Associated with Dysmorphic Features, Intellectual Disability, and Neurological Manifestations." American journal of human genetics 97.6 (December 2015): 922-932.
PMID
26637982
Source
epmc
Published In
The American Journal of Human Genetics
Volume
97
Issue
6
Publish Date
2015
Start Page
922
End Page
932
DOI
10.1016/j.ajhg.2015.11.005

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor.

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.

Authors
Hor, H; Francescatto, L; Bartesaghi, L; Ortega-Cubero, S; Kousi, M; Lorenzo-Betancor, O; Jiménez-Jiménez, FJ; Gironell, A; Clarimón, J; Drechsel, O; Agúndez, JAG; Kenzelmann Broz, D; Chiquet-Ehrismann, R; Lleó, A; Coria, F; García-Martin, E; Alonso-Navarro, H; Martí, MJ; Kulisevsky, J; Hor, CN; Ossowski, S; Chrast, R; Katsanis, N; Pastor, P; Estivill, X
MLA Citation
Hor, H, Francescatto, L, Bartesaghi, L, Ortega-Cubero, S, Kousi, M, Lorenzo-Betancor, O, Jiménez-Jiménez, FJ, Gironell, A, Clarimón, J, Drechsel, O, Agúndez, JAG, Kenzelmann Broz, D, Chiquet-Ehrismann, R, Lleó, A, Coria, F, García-Martin, E, Alonso-Navarro, H, Martí, MJ, Kulisevsky, J, Hor, CN, Ossowski, S, Chrast, R, Katsanis, N, Pastor, P, and Estivill, X. "Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor." Human molecular genetics 24.20 (October 2015): 5677-5686.
PMID
26188006
Source
epmc
Published In
Human Molecular Genetics
Volume
24
Issue
20
Publish Date
2015
Start Page
5677
End Page
5686
DOI
10.1093/hmg/ddv281

Neuroanatomical and behavioral deficits in mice haploinsufficient for Pericentriolar material 1 (Pcm1).

The pericentriolar material (PCM) is composed of proteins responsible for microtubule nucleation/anchoring at the centrosome, some of which have been associated with genetic susceptibility to schizophrenia. Here, we show that mice haploinsufficient for Pericentriolar material 1 (Pcm1(+/-)), which encodes a component of the PCM found to bear rare loss of function mutations in patients with psychiatric illness, manifest neuroanatomical phenotypes and behavioral abnormalities. Using ex vivo magnetic resonance imaging of the Pcm1(+/-) brain, we detect reduced whole brain volume. Pcm1 mutant mice show impairment in social interaction, specifically in the social novelty phase, but not in the sociability phase of the three-chamber social interaction test. In contrast, Pcm1(+/-) mice show normal preference for a novel object, suggesting specific impairment in response to novel social stimulus. In addition, Pcm1(+/-) mice display significantly reduced rearing activity in the open field. Pcm1(+/-) mice behave normally in the elevated plus maze, rotarod, prepulse inhibition, and progressive ratio tests. Together, our results suggest that haploinsufficiency at the Pcm1 locus can induce a range of neuroanatomical and behavioral phenotypes that support the candidacy of this locus in neuropsychiatric disorders.

Authors
Zoubovsky, S; Oh, EC; Cash-Padgett, T; Johnson, AW; Hou, Z; Mori, S; Gallagher, M; Katsanis, N; Sawa, A; Jaaro-Peled, H
MLA Citation
Zoubovsky, S, Oh, EC, Cash-Padgett, T, Johnson, AW, Hou, Z, Mori, S, Gallagher, M, Katsanis, N, Sawa, A, and Jaaro-Peled, H. "Neuroanatomical and behavioral deficits in mice haploinsufficient for Pericentriolar material 1 (Pcm1)." Neuroscience research 98 (September 2015): 45-49.
PMID
25697395
Source
epmc
Published In
Neuroscience Research
Volume
98
Publish Date
2015
Start Page
45
End Page
49
DOI
10.1016/j.neures.2015.02.002

RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome.

The genetic disorder Kabuki syndrome (KS) is characterized by developmental delay and congenital anomalies. Dominant mutations in the chromatin regulators lysine (K)-specific methyltransferase 2D (KMT2D) (also known as MLL2) and lysine (K)-specific demethylase 6A (KDM6A) underlie the majority of cases. Although the functions of these chromatin-modifying proteins have been studied extensively, the physiological systems regulated by them are largely unknown. Using whole-exome sequencing, we identified a mutation in RAP1A that was converted to homozygosity as the result of uniparental isodisomy (UPD) in a patient with KS and a de novo, dominant mutation in RAP1B in a second individual with a KS-like phenotype. We elucidated a genetic and functional interaction between the respective KS-associated genes and their products in zebrafish models and patient cell lines. Specifically, we determined that dysfunction of known KS genes and the genes identified in this study results in aberrant MEK/ERK signaling as well as disruption of F-actin polymerization and cell intercalation. Moreover, these phenotypes could be rescued in zebrafish models by rebalancing MEK/ERK signaling via administration of small molecule inhibitors of MEK. Taken together, our studies suggest that the KS pathophysiology overlaps with the RASopathies and provide a potential direction for treatment design.

Authors
Bögershausen, N; Tsai, I-C; Pohl, E; Kiper, PÖS; Beleggia, F; Percin, EF; Keupp, K; Matchan, A; Milz, E; Alanay, Y; Kayserili, H; Liu, Y; Banka, S; Kranz, A; Zenker, M; Wieczorek, D; Elcioglu, N; Prontera, P; Lyonnet, S; Meitinger, T; Stewart, AF; Donnai, D; Strom, TM; Boduroglu, K; Yigit, G; Li, Y; Katsanis, N; Wollnik, B
MLA Citation
Bögershausen, N, Tsai, I-C, Pohl, E, Kiper, PÖS, Beleggia, F, Percin, EF, Keupp, K, Matchan, A, Milz, E, Alanay, Y, Kayserili, H, Liu, Y, Banka, S, Kranz, A, Zenker, M, Wieczorek, D, Elcioglu, N, Prontera, P, Lyonnet, S, Meitinger, T, Stewart, AF, Donnai, D, Strom, TM, Boduroglu, K, Yigit, G, Li, Y, Katsanis, N, and Wollnik, B. "RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome." The Journal of clinical investigation 125.9 (September 2015): 3585-3599.
PMID
26280580
Source
epmc
Published In
Journal of Clinical Investigation
Volume
125
Issue
9
Publish Date
2015
Start Page
3585
End Page
3599
DOI
10.1172/jci80102

Transient laminin beta 1a Induction Defines the Wound Epidermis during Zebrafish Fin Regeneration.

The first critical stage in salamander or teleost appendage regeneration is creation of a specialized epidermis that instructs growth from underlying stump tissue. Here, we performed a forward genetic screen for mutations that impair this process in amputated zebrafish fins. Positional cloning and complementation assays identified a temperature-sensitive allele of the ECM component laminin beta 1a (lamb1a) that blocks fin regeneration. lamb1a, but not its paralog lamb1b, is sharply induced in a subset of epithelial cells after fin amputation, where it is required to establish and maintain a polarized basal epithelial cell layer. These events facilitate expression of the morphogenetic factors shha and lef1, basolateral positioning of phosphorylated Igf1r, patterning of new osteoblasts, and regeneration of bone. By contrast, lamb1a function is dispensable for juvenile body growth, homeostatic adult tissue maintenance, repair of split fins, or renewal of genetically ablated osteoblasts. fgf20a mutations or transgenic Fgf receptor inhibition disrupt lamb1a expression, linking a central growth factor to epithelial maturation during regeneration. Our findings reveal transient induction of lamb1a in epithelial cells as a key, growth factor-guided step in formation of a signaling-competent regeneration epidermis.

Authors
Chen, C-H; Merriman, AF; Savage, J; Willer, J; Wahlig, T; Katsanis, N; Yin, VP; Poss, KD
MLA Citation
Chen, C-H, Merriman, AF, Savage, J, Willer, J, Wahlig, T, Katsanis, N, Yin, VP, and Poss, KD. "Transient laminin beta 1a Induction Defines the Wound Epidermis during Zebrafish Fin Regeneration." PLoS genetics 11.8 (August 25, 2015): e1005437-.
PMID
26305099
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
8
Publish Date
2015
Start Page
e1005437
DOI
10.1371/journal.pgen.1005437

Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

Authors
Gonzaga-Jauregui, C; Harel, T; Gambin, T; Kousi, M; Griffin, LB; Francescatto, L; Ozes, B; Karaca, E; Jhangiani, SN; Bainbridge, MN; Lawson, KS; Pehlivan, D; Okamoto, Y; Withers, M; Mancias, P; Slavotinek, A; Reitnauer, PJ; Goksungur, MT; Shy, M; Crawford, TO; Koenig, M; Willer, J; Flores, BN; Pediaditrakis, I; Us, O; Wiszniewski, W; Parman, Y; Antonellis, A; Muzny, DM; Katsanis, N; Battaloglu, E; Boerwinkle, E; Gibbs, RA; Lupski, JR
MLA Citation
Gonzaga-Jauregui, C, Harel, T, Gambin, T, Kousi, M, Griffin, LB, Francescatto, L, Ozes, B, Karaca, E, Jhangiani, SN, Bainbridge, MN, Lawson, KS, Pehlivan, D, Okamoto, Y, Withers, M, Mancias, P, Slavotinek, A, Reitnauer, PJ, Goksungur, MT, Shy, M, Crawford, TO, Koenig, M, Willer, J, Flores, BN, Pediaditrakis, I, Us, O, Wiszniewski, W, Parman, Y, Antonellis, A, Muzny, DM, Katsanis, N, Battaloglu, E, Boerwinkle, E, Gibbs, RA, and Lupski, JR. "Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy." Cell reports 12.7 (August 5, 2015): 1169-1183.
PMID
26257172
Source
epmc
Published In
Cell Reports
Volume
12
Issue
7
Publish Date
2015
Start Page
1169
End Page
1183
DOI
10.1016/j.celrep.2015.07.023

Rapid and Efficient Generation of Transgene-Free iPSC from a Small Volume of Cryopreserved Blood.

Human peripheral blood and umbilical cord blood represent attractive sources of cells for reprogramming to induced pluripotent stem cells (iPSCs). However, to date, most of the blood-derived iPSCs were generated using either integrating methods or starting from T-lymphocytes that have genomic rearrangements thus bearing uncertain consequences when using iPSC-derived lineages for disease modeling and cell therapies. Recently, both peripheral blood and cord blood cells have been reprogrammed into transgene-free iPSC using the Sendai viral vector. Here we demonstrate that peripheral blood can be utilized for medium-throughput iPSC production without the need to maintain cell culture prior to reprogramming induction. Cell reprogramming can also be accomplished with as little as 3000 previously cryopreserved cord blood cells under feeder-free and chemically defined Xeno-free conditions that are compliant with standard Good Manufacturing Practice (GMP) regulations. The first iPSC colonies appear 2-3 weeks faster in comparison to previous reports. Notably, these peripheral blood- and cord blood-derived iPSCs are free of detectable immunoglobulin heavy chain (IGH) and T cell receptor (TCR) gene rearrangements, suggesting they did not originate from B- or T- lymphoid cells. The iPSCs are pluripotent as evaluated by the scorecard assay and in vitro multi lineage functional cell differentiation. Our data show that small volumes of cryopreserved peripheral blood or cord blood cells can be reprogrammed efficiently at a convenient, cost effective and scalable way. In summary, our method expands the reprogramming potential of limited or archived samples either stored at blood banks or obtained from pediatric populations that cannot easily provide large quantities of peripheral blood or a skin biopsy.

Authors
Zhou, H; Martinez, H; Sun, B; Li, A; Zimmer, M; Katsanis, N; Davis, EE; Kurtzberg, J; Lipnick, S; Noggle, S; Rao, M; Chang, S
MLA Citation
Zhou, H, Martinez, H, Sun, B, Li, A, Zimmer, M, Katsanis, N, Davis, EE, Kurtzberg, J, Lipnick, S, Noggle, S, Rao, M, and Chang, S. "Rapid and Efficient Generation of Transgene-Free iPSC from a Small Volume of Cryopreserved Blood." Stem cell reviews 11.4 (August 2015): 652-665.
PMID
25951995
Source
epmc
Published In
Stem Cell Reviews and Reports
Volume
11
Issue
4
Publish Date
2015
Start Page
652
End Page
665
DOI
10.1007/s12015-015-9586-8

Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction.

Left ventricular noncompaction (LVNC) is an autosomal-dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co-occur with cardiac hypertrophy.Here, we generated whole exome sequence data from multiple members from 5 families with LVNC. In 4 of 5 families, the candidate causative mutation segregates with disease in known LVNC genes MYH7 and TPM1. Subsequent sequencing of MYH7 in a larger LVNC cohort identified 7 novel likely disease causing variants. In the fifth family, we identified a frameshift mutation in NNT, a nuclear-encoded mitochondrial protein, not implicated previously in human cardiomyopathies. Resequencing of NNT in additional LVNC families identified a second likely pathogenic missense allele. Suppression of nnt in zebrafish caused early ventricular malformation and contractility defects, probably driven by altered cardiomyocyte proliferation. In vivo complementation studies showed that mutant human NNT failed to rescue nnt morpholino-induced heart dysfunction, indicating a probable haploinsufficiency mechanism.Together, our data expand the genetic spectrum of LVNC and demonstrate how the intersection of whole exome sequence with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.

Authors
Bainbridge, MN; Davis, EE; Choi, W-Y; Dickson, A; Martinez, HR; Wang, M; Dinh, H; Muzny, DM; Pignatelli, R; Katsanis, N; Boerwinkle, E; Gibbs, RA; Jefferies, JL
MLA Citation
Bainbridge, MN, Davis, EE, Choi, W-Y, Dickson, A, Martinez, HR, Wang, M, Dinh, H, Muzny, DM, Pignatelli, R, Katsanis, N, Boerwinkle, E, Gibbs, RA, and Jefferies, JL. "Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction." Circulation. Cardiovascular genetics 8.4 (August 2015): 544-552.
PMID
26025024
Source
epmc
Published In
Circulation: Cardiovascular Genetics
Volume
8
Issue
4
Publish Date
2015
Start Page
544
End Page
552
DOI
10.1161/circgenetics.115.001026

Identification of cis-suppression of human disease mutations by comparative genomics.

Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.

Authors
Jordan, DM; Frangakis, SG; Golzio, C; Cassa, CA; Kurtzberg, J; Davis, EE; Sunyaev, SR; Katsanis, N
MLA Citation
Jordan, DM, Frangakis, SG, Golzio, C, Cassa, CA, Kurtzberg, J, Davis, EE, Sunyaev, SR, and Katsanis, N. "Identification of cis-suppression of human disease mutations by comparative genomics." Nature 524.7564 (August 2015): 225-229.
PMID
26123021
Source
epmc
Published In
Nature
Volume
524
Issue
7564
Publish Date
2015
Start Page
225
End Page
229
DOI
10.1038/nature14497

Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Authors
Snijders Blok, L; Madsen, E; Juusola, J; Gilissen, C; Baralle, D; Reijnders, MRF; Venselaar, H; Helsmoortel, C; Cho, MT; Hoischen, A; Vissers, LELM; Koemans, TS; Wissink-Lindhout, W; Eichler, EE; Romano, C; Van Esch, H; Stumpel, C; Vreeburg, M; Smeets, E; Oberndorff, K; van Bon, BWM; Shaw, M; Gecz, J; Haan, E; Bienek, M; Jensen, C; Loeys, BL; Van Dijck, A; Innes, AM; Racher, H; Vermeer, S; Di Donato, N; Rump, A; Tatton-Brown, K; Parker, MJ; Henderson, A; Lynch, SA; Fryer, A; Ross, A et al.
MLA Citation
Snijders Blok, L, Madsen, E, Juusola, J, Gilissen, C, Baralle, D, Reijnders, MRF, Venselaar, H, Helsmoortel, C, Cho, MT, Hoischen, A, Vissers, LELM, Koemans, TS, Wissink-Lindhout, W, Eichler, EE, Romano, C, Van Esch, H, Stumpel, C, Vreeburg, M, Smeets, E, Oberndorff, K, van Bon, BWM, Shaw, M, Gecz, J, Haan, E, Bienek, M, Jensen, C, Loeys, BL, Van Dijck, A, Innes, AM, Racher, H, Vermeer, S, Di Donato, N, Rump, A, Tatton-Brown, K, Parker, MJ, Henderson, A, Lynch, SA, Fryer, A, and Ross, A et al. "Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling." American journal of human genetics 97.2 (August 2015): 343-352.
PMID
26235985
Source
epmc
Published In
The American Journal of Human Genetics
Volume
97
Issue
2
Publish Date
2015
Start Page
343
End Page
352
DOI
10.1016/j.ajhg.2015.07.004

In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.

African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.

Authors
Anderson, BR; Howell, DN; Soldano, K; Garrett, ME; Katsanis, N; Telen, MJ; Davis, EE; Ashley-Koch, AE
MLA Citation
Anderson, BR, Howell, DN, Soldano, K, Garrett, ME, Katsanis, N, Telen, MJ, Davis, EE, and Ashley-Koch, AE. "In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress." PLoS genetics 11.7 (July 6, 2015): e1005349-.
Website
http://hdl.handle.net/10161/10832
PMID
26147622
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
7
Publish Date
2015
Start Page
e1005349
DOI
10.1371/journal.pgen.1005349

Expansion of CTG18.1 Trinucleotide Repeat in TCF4 Is a Potent Driver of Fuchs' Corneal Dystrophy.

To analyze the expansion of CTG18.1 allele associated with Fuchs' corneal dystrophy (FCD) in our large cohort of late-onset FCD cases.CTG repeats within the CTG18.1 allele were estimated by short tandem repeat (STR) and triplet primed PCR (TP-PCR) assays in our large cohort of 574 late-onset FCD cases and 354 controls and large multigeneration familial cases. The age versus severity relationships were analyzed in FCD genotypes, namely, nonexpanded (N/N), monoallelic expansion (N/X), and biallelic expansion (X/X) with N ≤ 40 CTG monomers. The threshold for causality conferred by an expansion of CTG18.1 was identified by excluding the population of FCD cases who harbored an allele length equivalent to the maximum CTG monomers observed in the controls.The expanded CTG18.1 for (CTG)n>40 showed a strong association (P = 1.56 × 10(-82)) with FCD. Importantly, we delineated the threshold of expansion to 103 CTG repeats above which the allele confers causality in 17.8% of FCD cases. Regression analyses demonstrated a significant correlation between disease severity and age in individuals who harbor either a monoallelic expansion or a biallelic expansion at (CTG) n > 40. These analyses helped predict FCD in two previously unaffected individuals based on their CTG18.1 expansion genotype.A monoallelic expansion of CTG18.1 contributes to increased disease severity and is causal at (CTG)n>103, whereas a biallelic expansion is sufficient to be causal for FCD at (CTG)n>40. This study highlights the largest contributory causal allele for FCD.

Authors
Vasanth, S; Eghrari, AO; Gapsis, BC; Wang, J; Haller, NF; Stark, WJ; Katsanis, N; Riazuddin, SA; Gottsch, JD
MLA Citation
Vasanth, S, Eghrari, AO, Gapsis, BC, Wang, J, Haller, NF, Stark, WJ, Katsanis, N, Riazuddin, SA, and Gottsch, JD. "Expansion of CTG18.1 Trinucleotide Repeat in TCF4 Is a Potent Driver of Fuchs' Corneal Dystrophy." Investigative ophthalmology & visual science 56.8 (July 2015): 4531-4536.
PMID
26200491
Source
epmc
Published In
Investigative Ophthalmology and Visual Science
Volume
56
Issue
8
Publish Date
2015
Start Page
4531
End Page
4536
DOI
10.1167/iovs.14-16122

Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia.

Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.

Authors
Zech, M; Lam, DD; Francescatto, L; Schormair, B; Salminen, AV; Jochim, A; Wieland, T; Lichtner, P; Peters, A; Gieger, C; Lochmüller, H; Strom, TM; Haslinger, B; Katsanis, N; Winkelmann, J
MLA Citation
Zech, M, Lam, DD, Francescatto, L, Schormair, B, Salminen, AV, Jochim, A, Wieland, T, Lichtner, P, Peters, A, Gieger, C, Lochmüller, H, Strom, TM, Haslinger, B, Katsanis, N, and Winkelmann, J. "Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia." American journal of human genetics 96.6 (June 2015): 883-893.
PMID
26004199
Source
epmc
Published In
The American Journal of Human Genetics
Volume
96
Issue
6
Publish Date
2015
Start Page
883
End Page
893
DOI
10.1016/j.ajhg.2015.04.010

Genetic modifiers and oligogenic inheritance.

Despite remarkable progress in the identification of mutations that drive genetic disorders, progress in understanding the effect of genetic background on the penetrance and expressivity of causal alleles has been modest, in part because of the methodological challenges in identifying genetic modifiers. Nonetheless, the progressive discovery of modifier alleles has improved both our interpretative ability and our analytical tools to dissect such phenomena. In this review, we analyze the genetic properties and behaviors of modifiers as derived from studies in patient populations and model organisms and we highlight conceptual and technological tools used to overcome some of the challenges inherent in modifier mapping and cloning. Finally, we discuss how the identification of these modifiers has facilitated the elucidation of biological pathways and holds the potential to improve the clinical predictive value of primary causal mutations and to develop novel drug targets.

Authors
Kousi, M; Katsanis, N
MLA Citation
Kousi, M, and Katsanis, N. "Genetic modifiers and oligogenic inheritance." Cold Spring Harbor perspectives in medicine 5.6 (June 2015). (Review)
PMID
26033081
Source
epmc
Published In
Cold Spring Harbor perspectives in medicine
Volume
5
Issue
6
Publish Date
2015
DOI
10.1101/cshperspect.a017145

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies.

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing development.

Authors
Niceta, M; Stellacci, E; Gripp, KW; Zampino, G; Kousi, M; Anselmi, M; Traversa, A; Ciolfi, A; Stabley, D; Bruselles, A; Caputo, V; Cecchetti, S; Prudente, S; Fiorenza, MT; Boitani, C; Philip, N; Niyazov, D; Leoni, C; Nakane, T; Keppler-Noreuil, K; Braddock, SR; Gillessen-Kaesbach, G; Palleschi, A; Campeau, PM; Lee, BHL; Pouponnot, C; Stella, L; Bocchinfuso, G; Katsanis, N; Sol-Church, K; Tartaglia, M
MLA Citation
Niceta, M, Stellacci, E, Gripp, KW, Zampino, G, Kousi, M, Anselmi, M, Traversa, A, Ciolfi, A, Stabley, D, Bruselles, A, Caputo, V, Cecchetti, S, Prudente, S, Fiorenza, MT, Boitani, C, Philip, N, Niyazov, D, Leoni, C, Nakane, T, Keppler-Noreuil, K, Braddock, SR, Gillessen-Kaesbach, G, Palleschi, A, Campeau, PM, Lee, BHL, Pouponnot, C, Stella, L, Bocchinfuso, G, Katsanis, N, Sol-Church, K, and Tartaglia, M. "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies." American journal of human genetics 96.5 (May 2015): 816-825.
PMID
25865493
Source
epmc
Published In
The American Journal of Human Genetics
Volume
96
Issue
5
Publish Date
2015
Start Page
816
End Page
825
DOI
10.1016/j.ajhg.2015.03.001

A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

Authors
Migliavacca, E; Golzio, C; Männik, K; Blumenthal, I; Oh, EC; Harewood, L; Kosmicki, JA; Loviglio, MN; Giannuzzi, G; Hippolyte, L; Maillard, AM; Alfaiz, AA; van Haelst, MM; Andrieux, J; Gusella, JF; Daly, MJ; Beckmann, JS; Jacquemont, S; Talkowski, ME; Katsanis, N; Reymond, A
MLA Citation
Migliavacca, E, Golzio, C, Männik, K, Blumenthal, I, Oh, EC, Harewood, L, Kosmicki, JA, Loviglio, MN, Giannuzzi, G, Hippolyte, L, Maillard, AM, Alfaiz, AA, van Haelst, MM, Andrieux, J, Gusella, JF, Daly, MJ, Beckmann, JS, Jacquemont, S, Talkowski, ME, Katsanis, N, and Reymond, A. "A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology." American journal of human genetics 96.5 (May 2015): 784-796.
PMID
25937446
Source
epmc
Published In
The American Journal of Human Genetics
Volume
96
Issue
5
Publish Date
2015
Start Page
784
End Page
796
DOI
10.1016/j.ajhg.2015.04.002

Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly.

The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of the 1q21.1 locus has been implicated in the etiology of neurodevelopmental phenotypes; however, the role of 1q21.1 genes in neurogenesis has remained elusive. Here, we show that haploinsufficiency for Rbm8a, an exon junction complex (EJC) component within 1q21.1, causes severe microcephaly and defective neurogenesis in the mouse. At the onset of neurogenesis, Rbm8a regulates radial glia proliferation and prevents premature neuronal differentiation. Reduced Rbm8a levels result in subsequent apoptosis of neurons, and to a lesser extent, radial glia. Hence, compared to control, Rbm8a-haploinsufficient brains have fewer progenitors and neurons, resulting in defective cortical lamination. To determine whether reciprocal dosage change of Rbm8a alters embryonic neurogenesis, we overexpressed human RBM8A in two animal models. Using in utero electroporation of mouse neocortices as well as zebrafish models, we find RBM8A overexpression does not significantly perturb progenitor number or head size. Our findings demonstrate that Rbm8a is an essential neurogenesis regulator, and add to a growing literature highlighting roles for EJC components in cortical development and neurodevelopmental pathology. Our results indicate that disruption of RBM8A may contribute to neurodevelopmental phenotypes associated with proximal 1q21.1 microdeletions.

Authors
Mao, H; Pilaz, L-J; McMahon, JJ; Golzio, C; Wu, D; Shi, L; Katsanis, N; Silver, DL
MLA Citation
Mao, H, Pilaz, L-J, McMahon, JJ, Golzio, C, Wu, D, Shi, L, Katsanis, N, and Silver, DL. "Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly." The Journal of neuroscience : the official journal of the Society for Neuroscience 35.18 (May 2015): 7003-7018.
PMID
25948253
Source
epmc
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
35
Issue
18
Publish Date
2015
Start Page
7003
End Page
7018
DOI
10.1523/jneurosci.0018-15.2015

Mutations in the endothelin receptor type a cause mandibulofacial dysostosis with alopecia

© 2015 The American Society of Human Genetics.The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

Authors
Gordon, CT; Weaver, KN; Zechi-Ceide, RM; Madsen, EC; Tavares, ALP; Oufadem, M; Kurihara, Y; Adameyko, I; Picard, A; Breton, S; Pierrot, S; Biosse-Duplan, M; Voisin, N; Masson, C; Bole-Feysot, C; Nitschké, P; Delrue, MA; Lacombe, D; Guion-Almeida, ML; Moura, PP; Garib, DG; Munnich, A; Ernfors, P; Hufnagel, RB; Hopkin, RJ; Kurihara, H; Saal, HM; Weaver, DD; Katsanis, N; Lyonnet, S; Golzio, C; Clouthier, DE; Amiel, J
MLA Citation
Gordon, CT, Weaver, KN, Zechi-Ceide, RM, Madsen, EC, Tavares, ALP, Oufadem, M, Kurihara, Y, Adameyko, I, Picard, A, Breton, S, Pierrot, S, Biosse-Duplan, M, Voisin, N, Masson, C, Bole-Feysot, C, Nitschké, P, Delrue, MA, Lacombe, D, Guion-Almeida, ML, Moura, PP, Garib, DG, Munnich, A, Ernfors, P, Hufnagel, RB, Hopkin, RJ, Kurihara, H, Saal, HM, Weaver, DD, Katsanis, N, Lyonnet, S, Golzio, C, Clouthier, DE, and Amiel, J. "Mutations in the endothelin receptor type a cause mandibulofacial dysostosis with alopecia." American Journal of Human Genetics 96.4 (April 2, 2015): 519-531.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
96
Issue
4
Publish Date
2015
Start Page
519
End Page
531
DOI
10.1016/j.ajhg.2015.01.015

A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS.

FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS.

Authors
Hall, G; Gbadegesin, RA; Lavin, P; Wu, G; Liu, Y; Oh, EC; Wang, L; Spurney, RF; Eckel, J; Lindsey, T; Homstad, A; Malone, AF; Phelan, PJ; Shaw, A; Howell, DN; Conlon, PJ; Katsanis, N; Winn, MP
MLA Citation
Hall, G, Gbadegesin, RA, Lavin, P, Wu, G, Liu, Y, Oh, EC, Wang, L, Spurney, RF, Eckel, J, Lindsey, T, Homstad, A, Malone, AF, Phelan, PJ, Shaw, A, Howell, DN, Conlon, PJ, Katsanis, N, and Winn, MP. "A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS." Journal of the American Society of Nephrology : JASN 26.4 (April 2015): 831-843.
PMID
25145932
Source
epmc
Published In
Journal of the American Society of Nephrology : JASN
Volume
26
Issue
4
Publish Date
2015
Start Page
831
End Page
843
DOI
10.1681/asn.2013101053

Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers.We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed.We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens.Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.

Authors
Bonora, E; Bianco, F; Cordeddu, L; Bamshad, M; Francescatto, L; Dowless, D; Stanghellini, V; Cogliandro, RF; Lindberg, G; Mungan, Z; Cefle, K; Ozcelik, T; Palanduz, S; Ozturk, S; Gedikbasi, A; Gori, A; Pippucci, T; Graziano, C; Volta, U; Caio, G; Barbara, G; D'Amato, M; Seri, M; Katsanis, N; Romeo, G; De Giorgio, R
MLA Citation
Bonora, E, Bianco, F, Cordeddu, L, Bamshad, M, Francescatto, L, Dowless, D, Stanghellini, V, Cogliandro, RF, Lindberg, G, Mungan, Z, Cefle, K, Ozcelik, T, Palanduz, S, Ozturk, S, Gedikbasi, A, Gori, A, Pippucci, T, Graziano, C, Volta, U, Caio, G, Barbara, G, D'Amato, M, Seri, M, Katsanis, N, Romeo, G, and De Giorgio, R. "Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction." Gastroenterology 148.4 (April 2015): 771-782.e11.
PMID
25575569
Source
epmc
Published In
Gastroenterology
Volume
148
Issue
4
Publish Date
2015
Start Page
771
End Page
782.e11
DOI
10.1053/j.gastro.2014.12.034

Loss of δ-catenin function in severe autism.

Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.

Authors
Turner, TN; Sharma, K; Oh, EC; Liu, YP; Collins, RL; Collins, RL; Sosa, MX; Auer, DR; Brand, H; Sanders, SJ; Moreno-De-Luca, D; Pihur, V; Plona, T; Pike, K; Soppet, DR; Smith, MW; Cheung, SW; Martin, CL; State, MW; Talkowski, ME; Cook, E; Huganir, R; Katsanis, N; Chakravarti, A
MLA Citation
Turner, TN, Sharma, K, Oh, EC, Liu, YP, Collins, RL, Collins, RL, Sosa, MX, Auer, DR, Brand, H, Sanders, SJ, Moreno-De-Luca, D, Pihur, V, Plona, T, Pike, K, Soppet, DR, Smith, MW, Cheung, SW, Martin, CL, State, MW, Talkowski, ME, Cook, E, Huganir, R, Katsanis, N, and Chakravarti, A. "Loss of δ-catenin function in severe autism." Nature 520.7545 (April 2015): 51-56.
PMID
25807484
Source
epmc
Published In
Nature
Volume
520
Issue
7545
Publish Date
2015
Start Page
51
End Page
56
DOI
10.1038/nature14186

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia.

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

Authors
Gordon, CT; Weaver, KN; Zechi-Ceide, RM; Madsen, EC; Tavares, ALP; Oufadem, M; Kurihara, Y; Adameyko, I; Picard, A; Breton, S; Pierrot, S; Biosse-Duplan, M; Voisin, N; Masson, C; Bole-Feysot, C; Nitschké, P; Delrue, M-A; Lacombe, D; Guion-Almeida, ML; Moura, PP; Garib, DG; Munnich, A; Ernfors, P; Hufnagel, RB; Hopkin, RJ; Kurihara, H; Saal, HM; Weaver, DD; Katsanis, N; Lyonnet, S; Golzio, C; Clouthier, DE; Amiel, J
MLA Citation
Gordon, CT, Weaver, KN, Zechi-Ceide, RM, Madsen, EC, Tavares, ALP, Oufadem, M, Kurihara, Y, Adameyko, I, Picard, A, Breton, S, Pierrot, S, Biosse-Duplan, M, Voisin, N, Masson, C, Bole-Feysot, C, Nitschké, P, Delrue, M-A, Lacombe, D, Guion-Almeida, ML, Moura, PP, Garib, DG, Munnich, A, Ernfors, P, Hufnagel, RB, Hopkin, RJ, Kurihara, H, Saal, HM, Weaver, DD, Katsanis, N, Lyonnet, S, Golzio, C, Clouthier, DE, and Amiel, J. "Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia." American journal of human genetics 96.4 (April 2015): 519-531.
PMID
25772936
Source
epmc
Published In
The American Journal of Human Genetics
Volume
96
Issue
4
Publish Date
2015
Start Page
519
End Page
531
DOI
10.1016/j.ajhg.2015.01.015

TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone.

The Meckel syndrome (MKS) complex functions at the transition zone, located between the basal body and axoneme, to regulate the localization of ciliary membrane proteins. We investigated the role of Tmem231, a two-pass transmembrane protein, in MKS complex formation and function. Consistent with a role in transition zone function, mutation of mouse Tmem231 disrupts the localization of proteins including Arl13b and Inpp5e to cilia, resulting in phenotypes characteristic of MKS such as polydactyly and kidney cysts. Tmem231 and B9d1 are essential for each other and other complex components such as Mks1 to localize to the transition zone. As in mouse, the Caenorhabditis elegans orthologue of Tmem231 localizes to and controls transition zone formation and function, suggesting an evolutionarily conserved role for Tmem231. We identified TMEM231 mutations in orofaciodigital syndrome type 3 (OFD3) and MKS patients that compromise transition zone function. Thus, Tmem231 is critical for organizing the MKS complex and controlling ciliary composition, defects in which cause OFD3 and MKS.

Authors
Roberson, EC; Dowdle, WE; Ozanturk, A; Garcia-Gonzalo, FR; Li, C; Halbritter, J; Elkhartoufi, N; Porath, JD; Cope, H; Ashley-Koch, A; Gregory, S; Thomas, S; Sayer, JA; Saunier, S; Otto, EA; Katsanis, N; Davis, EE; Attié-Bitach, T; Hildebrandt, F; Leroux, MR; Reiter, JF
MLA Citation
Roberson, EC, Dowdle, WE, Ozanturk, A, Garcia-Gonzalo, FR, Li, C, Halbritter, J, Elkhartoufi, N, Porath, JD, Cope, H, Ashley-Koch, A, Gregory, S, Thomas, S, Sayer, JA, Saunier, S, Otto, EA, Katsanis, N, Davis, EE, Attié-Bitach, T, Hildebrandt, F, Leroux, MR, and Reiter, JF. "TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone." The Journal of cell biology 209.1 (April 2015): 129-142.
PMID
25869670
Source
epmc
Published In
The Journal of Cell Biology
Volume
209
Issue
1
Publish Date
2015
Start Page
129
End Page
142
DOI
10.1083/jcb.201411087

The Bardet-Biedl and orofacial digital type 1 ciliopathies

Authors
Franco, B; Katsanis, N
MLA Citation
Franco, B, and Katsanis, N. "The Bardet-Biedl and orofacial digital type 1 ciliopathies." Polycystic Kidney Disease: From Bench to Bedside. March 1, 2015. 91-112.
Source
scopus
Publish Date
2015
Start Page
91
End Page
112
DOI
10.2217/EBO.13.92

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Authors
Waters, AM; Asfahani, R; Carroll, P; Bicknell, L; Lescai, F; Bright, A; Chanudet, E; Brooks, A; Christou-Savina, S; Osman, G; Walsh, P; Bacchelli, C; Chapgier, A; Vernay, B; Bader, DM; Deshpande, C; O' Sullivan, M; Ocaka, L; Stanescu, H; Stewart, HS; Hildebrandt, F; Otto, E; Johnson, CA; Szymanska, K; Katsanis, N; Davis, E; Kleta, R; Hubank, M; Doxsey, S; Jackson, A; Stupka, E; Winey, M; Beales, PL
MLA Citation
Waters, AM, Asfahani, R, Carroll, P, Bicknell, L, Lescai, F, Bright, A, Chanudet, E, Brooks, A, Christou-Savina, S, Osman, G, Walsh, P, Bacchelli, C, Chapgier, A, Vernay, B, Bader, DM, Deshpande, C, O' Sullivan, M, Ocaka, L, Stanescu, H, Stewart, HS, Hildebrandt, F, Otto, E, Johnson, CA, Szymanska, K, Katsanis, N, Davis, E, Kleta, R, Hubank, M, Doxsey, S, Jackson, A, Stupka, E, Winey, M, and Beales, PL. "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes." Journal of medical genetics 52.3 (March 2015): 147-156.
PMID
25564561
Source
epmc
Published In
Journal of medical genetics
Volume
52
Issue
3
Publish Date
2015
Start Page
147
End Page
156
DOI
10.1136/jmedgenet-2014-102691

Epigenetic control of intestinal barrier function and inflammation in zebrafish.

The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.

Authors
Marjoram, L; Alvers, A; Deerhake, ME; Bagwell, J; Mankiewicz, J; Cocchiaro, JL; Beerman, RW; Willer, J; Sumigray, KD; Katsanis, N; Tobin, DM; Rawls, JF; Goll, MG; Bagnat, M
MLA Citation
Marjoram, L, Alvers, A, Deerhake, ME, Bagwell, J, Mankiewicz, J, Cocchiaro, JL, Beerman, RW, Willer, J, Sumigray, KD, Katsanis, N, Tobin, DM, Rawls, JF, Goll, MG, and Bagnat, M. "Epigenetic control of intestinal barrier function and inflammation in zebrafish." Proceedings of the National Academy of Sciences of the United States of America 112.9 (March 2015): 2770-2775.
PMID
25730872
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
112
Issue
9
Publish Date
2015
Start Page
2770
End Page
2775
DOI
10.1073/pnas.1424089112

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

© 2015 The American Society of Human Genetics.We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.

Authors
Wortmann, SB; Ziętkiewicz, S; Kousi, M; Szklarczyk, R; Haack, TB; Gersting, SW; Muntau, AC; Rakovic, A; Renkema, GH; Rodenburg, RJ; Strom, TM; Meitinger, T; Rubio-Gozalbo, ME; Chrusciel, E; Distelmaier, F; Golzio, C; Jansen, JH; Van Karnebeek, C; Lillquist, Y; Lücke, T; Õunap, K; Zordania, R; Yaplito-Lee, J; Van Bokhoven, H; Spelbrink, JN; Vaz, FM; Pras-Raves, M; Ploski, R; Pronicka, E; Klein, C; Willemsen, MAAP; De Brouwer, APM; Prokisch, H; Katsanis, N; Wevers, RA
MLA Citation
Wortmann, SB, Ziętkiewicz, S, Kousi, M, Szklarczyk, R, Haack, TB, Gersting, SW, Muntau, AC, Rakovic, A, Renkema, GH, Rodenburg, RJ, Strom, TM, Meitinger, T, Rubio-Gozalbo, ME, Chrusciel, E, Distelmaier, F, Golzio, C, Jansen, JH, Van Karnebeek, C, Lillquist, Y, Lücke, T, Õunap, K, Zordania, R, Yaplito-Lee, J, Van Bokhoven, H, Spelbrink, JN, Vaz, FM, Pras-Raves, M, Ploski, R, Pronicka, E, Klein, C, Willemsen, MAAP, De Brouwer, APM, Prokisch, H, Katsanis, N, and Wevers, RA. "CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder." American Journal of Human Genetics 96.2 (February 5, 2015): 245-257.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
96
Issue
2
Publish Date
2015
Start Page
245
End Page
257
DOI
10.1016/j.ajhg.2014.12.013

BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.

Authors
Borck, G; Hög, F; Dentici, ML; Tan, PL; Sowada, N; Medeira, A; Gueneau, L; Thiele, H; Kousi, M; Lepri, F; Wenzeck, L; Blumenthal, I; Radicioni, A; Schwarzenberg, TL; Mandriani, B; Fischetto, R; Morris-Rosendahl, DJ; Altmüller, J; Reymond, A; Nürnberg, P; Merla, G; Dallapiccola, B; Katsanis, N; Cramer, P; Kubisch, C
MLA Citation
Borck, G, Hög, F, Dentici, ML, Tan, PL, Sowada, N, Medeira, A, Gueneau, L, Thiele, H, Kousi, M, Lepri, F, Wenzeck, L, Blumenthal, I, Radicioni, A, Schwarzenberg, TL, Mandriani, B, Fischetto, R, Morris-Rosendahl, DJ, Altmüller, J, Reymond, A, Nürnberg, P, Merla, G, Dallapiccola, B, Katsanis, N, Cramer, P, and Kubisch, C. "BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies." Genome research 25.2 (February 2015): 155-166.
PMID
25561519
Source
epmc
Published In
Genome research
Volume
25
Issue
2
Publish Date
2015
Start Page
155
End Page
166
DOI
10.1101/gr.176925.114

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder.

We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria.

Authors
Wortmann, SB; Ziętkiewicz, S; Kousi, M; Szklarczyk, R; Haack, TB; Gersting, SW; Muntau, AC; Rakovic, A; Renkema, GH; Rodenburg, RJ; Strom, TM; Meitinger, T; Rubio-Gozalbo, ME; Chrusciel, E; Distelmaier, F; Golzio, C; Jansen, JH; van Karnebeek, C; Lillquist, Y; Lücke, T; Õunap, K; Zordania, R; Yaplito-Lee, J; van Bokhoven, H; Spelbrink, JN; Vaz, FM; Pras-Raves, M; Ploski, R; Pronicka, E; Klein, C; Willemsen, MAAP; de Brouwer, APM; Prokisch, H; Katsanis, N; Wevers, RA
MLA Citation
Wortmann, SB, Ziętkiewicz, S, Kousi, M, Szklarczyk, R, Haack, TB, Gersting, SW, Muntau, AC, Rakovic, A, Renkema, GH, Rodenburg, RJ, Strom, TM, Meitinger, T, Rubio-Gozalbo, ME, Chrusciel, E, Distelmaier, F, Golzio, C, Jansen, JH, van Karnebeek, C, Lillquist, Y, Lücke, T, Õunap, K, Zordania, R, Yaplito-Lee, J, van Bokhoven, H, Spelbrink, JN, Vaz, FM, Pras-Raves, M, Ploski, R, Pronicka, E, Klein, C, Willemsen, MAAP, de Brouwer, APM, Prokisch, H, Katsanis, N, and Wevers, RA. "CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder." American journal of human genetics 96.2 (February 2015): 245-257.
PMID
25597510
Source
epmc
Published In
The American Journal of Human Genetics
Volume
96
Issue
2
Publish Date
2015
Start Page
245
End Page
257
DOI
10.1016/j.ajhg.2014.12.013

Errata: BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies (Genome Research (2015) 25 (155-166))

Authors
Borck, G; Hög, F; Dentici, ML; Tan, PL; Sowada, N; Medeira, A; Gueneau, L; Thiele, H; Kousi, M; Lepri, F; Wenzeck, L; Blumenthal, I; Radicioni, A; Schwarzenberg, TL; Mandriani, B; Fischetto, R; Morris-Rosendahl, DJ; Altmüller, J; Reymond, A; Nürnberg, P; Merla, G; Dallapiccola, B; Katsanis, N; Cramer, P; Kubisch, C
MLA Citation
Borck, G, Hög, F, Dentici, ML, Tan, PL, Sowada, N, Medeira, A, Gueneau, L, Thiele, H, Kousi, M, Lepri, F, Wenzeck, L, Blumenthal, I, Radicioni, A, Schwarzenberg, TL, Mandriani, B, Fischetto, R, Morris-Rosendahl, DJ, Altmüller, J, Reymond, A, Nürnberg, P, Merla, G, Dallapiccola, B, Katsanis, N, Cramer, P, and Kubisch, C. "Errata: BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies (Genome Research (2015) 25 (155-166))." Genome Research 25.4 (January 1, 2015): 609-.
Source
scopus
Published In
Genome research
Volume
25
Issue
4
Publish Date
2015
Start Page
609

Metabolic regulation and energy homeostasis through the primary Cilium.

Obesity and diabetes represent a significant healthcare concern. In contrast to genome-wide association studies that, some exceptions notwithstanding, have offered modest clues about pathomechanism, the dissection of rare disorders in which obesity represents a core feature have highlighted key molecules and structures critical to energy regulation. Here we focus on the primary cilium, an organelle whose roles in energy homeostasis have been underscored by the high incidence of obesity and type II diabetes in patients and mouse mutants with compromised ciliary function. We discuss recent evidence linking ciliary dysfunction to metabolic defects and we explore the contribution of neuronal and nonneuronal cilia to these phenotypes.

Authors
Oh, EC; Vasanth, S; Katsanis, N
MLA Citation
Oh, EC, Vasanth, S, and Katsanis, N. "Metabolic regulation and energy homeostasis through the primary Cilium." Cell metabolism 21.1 (January 2015): 21-31. (Review)
PMID
25543293
Source
epmc
Published In
Cell Metabolism
Volume
21
Issue
1
Publish Date
2015
Start Page
21
End Page
31
DOI
10.1016/j.cmet.2014.11.019

Unique among ciliopathies: primary ciliary dyskinesia, a motile cilia disorder.

Primary ciliary dyskinesia (PCD) is a ciliopathy, but represents the sole entity from this class of disorders that results from the dysfunction of motile cilia. Characterized by respiratory problems appearing in childhood, infertility, and situs defects in ~50% of individuals, PCD has an estimated prevalence of approximately 1 in 10,000 live births. The diagnosis of PCD can be prolonged due to a lack of disease awareness, coupled with the fact that symptoms can be confused with other more common genetic disorders, such as cystic fibrosis, or environmental insults that result in frequent respiratory infections. A primarily autosomal recessive disorder, PCD is genetically heterogeneous with >30 causal genes identified, posing significant challenges to genetic diagnosis. Here, we provide an overview of PCD as a disorder underscored by impaired ciliary motility; we discuss the recent advances towards uncovering the genetic basis of PCD; we discuss the molecular knowledge gained from PCD gene discovery, which has improved our understanding of motile ciliary assembly; and we speculate on how accelerated diagnosis, together with detailed phenotypic data, will shape the genetic and functional architecture of this disorder.

Authors
Praveen, K; Davis, EE; Katsanis, N
MLA Citation
Praveen, K, Davis, EE, and Katsanis, N. "Unique among ciliopathies: primary ciliary dyskinesia, a motile cilia disorder." F1000prime reports 7 (January 2015): 36-. (Review)
PMID
25926987
Source
epmc
Published In
F1000 Prime Reports
Volume
7
Publish Date
2015
Start Page
36
DOI
10.12703/p7-36

Phosphorylation of Threonine 794 on Tie1 by Rac1/PAK1 Reveals a Novel Angiogenesis Regulatory Pathway.

The endothelial receptor tyrosine kinase (RTK) Tie1 was discovered over 20 years ago, yet its precise function and mode of action remain enigmatic. To shed light on Tie1's role in endothelial cell biology, we investigated a potential threonine phosphorylation site within the juxtamembrane domain of Tie1. Expression of a non-phosphorylatable mutant of this site (T794A) in zebrafish (Danio rerio) significantly disrupted vascular development, resulting in fish with stunted and poorly branched intersomitic vessels. Similarly, T794A-expressing human umbilical vein endothelial cells formed significantly shorter tubes with fewer branches in three-dimensional Matrigel cultures. However, mutation of T794 did not alter Tie1 or Tie2 tyrosine phosphorylation or downstream signaling in any detectable way, suggesting that T794 phosphorylation may regulate a Tie1 function independent of its RTK properties. Although T794 is within a consensus Akt phosphorylation site, we were unable to identify a physiological activator of Akt that could induce T794 phosphorylation, suggesting that Akt is not the physiological Tie1-T794 kinase. However, the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for angiogenesis and capillary morphogenesis, was found to associate with phospho-T794 but not the non-phosphorylatable T794A mutant. Pharmacological activation of Rac1 induced downstream activation of p21-activated kinase (PAK1) and T794 phosphorylation in vitro, and inhibition of PAK1 abrogated T794 phosphorylation. Our results provide the first demonstration of a signaling pathway mediated by Tie1 in endothelial cells, and they suggest that a novel feedback loop involving Rac1/PAK1 mediated phosphorylation of Tie1 on T794 is required for proper angiogenesis.

Authors
Reinardy, JL; Corey, DM; Golzio, C; Mueller, SB; Katsanis, N; Kontos, CD
MLA Citation
Reinardy, JL, Corey, DM, Golzio, C, Mueller, SB, Katsanis, N, and Kontos, CD. "Phosphorylation of Threonine 794 on Tie1 by Rac1/PAK1 Reveals a Novel Angiogenesis Regulatory Pathway." PloS one 10.10 (January 2015): e0139614-.
PMID
26436659
Source
epmc
Published In
PloS one
Volume
10
Issue
10
Publish Date
2015
Start Page
e0139614
DOI
10.1371/journal.pone.0139614

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes

Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. Methods and results: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. Conclusions: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Authors
Waters, AM; Asfahani, R; Carroll, P; Bicknell, L; Lescai, F; Bright, A; Chanudet, E; Brooks, A; Christou-Savina, S; Osman, G; Walsh, P; Bacchelli, C; Chapgier, A; Vernay, B; Bader, DM; Deshpande, C; O'Sullivan, M; Ocaka, L; Stanescu, H; Stewart, HS; Hildebrandt, F; Otto, E; Johnson, CA; Szymanska, K; Katsanis, N; Davis, E; Kleta, R; Hubank, M; Doxsey, S; Jackson, A; Stupka, E; Winey, M; Beales, PL
MLA Citation
Waters, AM, Asfahani, R, Carroll, P, Bicknell, L, Lescai, F, Bright, A, Chanudet, E, Brooks, A, Christou-Savina, S, Osman, G, Walsh, P, Bacchelli, C, Chapgier, A, Vernay, B, Bader, DM, Deshpande, C, O'Sullivan, M, Ocaka, L, Stanescu, H, Stewart, HS, Hildebrandt, F, Otto, E, Johnson, CA, Szymanska, K, Katsanis, N, Davis, E, Kleta, R, Hubank, M, Doxsey, S, Jackson, A, Stupka, E, Winey, M, and Beales, PL. "The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes." Journal of Medical Genetics 52.3 (2015): 147-156.
Source
scival
Published In
Journal of medical genetics
Volume
52
Issue
3
Publish Date
2015
Start Page
147
End Page
156
DOI
10.1136/jmedgenet-2014-102691

Rapid and efficient generation of transgene-free iPSC from a small volume of cryopreserved blood

© The Author(s) 2015.Human peripheral blood and umbilical cord blood represent attractive sources of cells for reprogramming to induced pluripotent stem cells (iPSCs). However, to date, most of the blood-derived iPSCs were generated using either integrating methods or starting from T-lymphocytes that have genomic rearrangements thus bearing uncertain consequences when using iPSC-derived lineages for disease modeling and cell therapies. Recently, both peripheral blood and cord blood cells have been reprogrammed into transgene-free iPSC using the Sendai viral vector. Here we demonstrate that peripheral blood can be utilized formedium-throughput iPSC production without the need to maintain cell culture prior to reprogramming induction. Cell reprogramming can also be accomplished with as little as 3000 previously cryopreserved cord blood cells under feeder-free and chemically defined Xeno-free conditions that are compliant with standard Good Manufacturing Practice (GMP) regulations. The first iPSC colonies appear 2–3 weeks faster in comparison to previous reports. Notably, these peripheral blood- and cord bloodderived iPSCs are free of detectable immunoglobulin heavy chain (IGH) and T cell receptor (TCR) gene rearrangements, suggesting they did not originate from B- or T- lymphoid cells. The iPSCs are pluripotent as evaluated by the scorecard assay and in vitro multi lineage functional cell differentiation. Our data show that small volumes of cryopreserved peripheral blood or cord blood cells can be reprogrammed efficiently at a convenient, cost effective and scalable way. In summary, our method expands the reprogramming potential of limited or archived samples either stored at blood banks or obtained from pediatric populations that cannot easily provide large quantities of peripheral blood or a skin biopsy.

Authors
Zhou, H; Martinez, H; Sun, B; Li, A; Zimmer, M; Katsanis, N; Davis, EE; Kurtzberg, J; Lipnick, S; Noggle, S; Rao, M; Chang, S
MLA Citation
Zhou, H, Martinez, H, Sun, B, Li, A, Zimmer, M, Katsanis, N, Davis, EE, Kurtzberg, J, Lipnick, S, Noggle, S, Rao, M, and Chang, S. "Rapid and efficient generation of transgene-free iPSC from a small volume of cryopreserved blood." Stem Cell Reviews and Reports 11.4 (2015): 652-665.
Source
scival
Published In
Stem Cell Reviews and Reports
Volume
11
Issue
4
Publish Date
2015
Start Page
652
End Page
665
DOI
10.1007/s12015-015-9586-8

From proteomic data to networks: statistics and methods reveal ciliary protein interaction landscape

Authors
Lu, Q; Koutroumpas, K; Boldt, K; Reeuwijk, J; Katsanis, N; Képès, F; Roepman, R; Ueffing, M; Russell, RB
MLA Citation
Lu, Q, Koutroumpas, K, Boldt, K, Reeuwijk, J, Katsanis, N, Képès, F, Roepman, R, Ueffing, M, and Russell, RB. "From proteomic data to networks: statistics and methods reveal ciliary protein interaction landscape." Cilia 4.Suppl 1 (2015): P90-P90.
Source
crossref
Published In
Cilia
Volume
4
Issue
Suppl 1
Publish Date
2015
Start Page
P90
End Page
P90
DOI
10.1186/2046-2530-4-S1-P90

Systematic exploration of the ciliary protein landscape by large-scale affinity proteomics

Authors
Boldt, K; Van Reeuwijk, J; Lu, Q; Koutroumpas, K; Horn, N; Beersum, S; Texier, Y; Nguyen, TM; Willer, JR; Katsanis, N; Képès, F; Russell, RB; Ueffing, M; Roepman, R
MLA Citation
Boldt, K, Van Reeuwijk, J, Lu, Q, Koutroumpas, K, Horn, N, Beersum, S, Texier, Y, Nguyen, TM, Willer, JR, Katsanis, N, Képès, F, Russell, RB, Ueffing, M, and Roepman, R. "Systematic exploration of the ciliary protein landscape by large-scale affinity proteomics." Cilia 4.Suppl 1 (2015): P89-P89.
Source
crossref
Published In
Cilia
Volume
4
Issue
Suppl 1
Publish Date
2015
Start Page
P89
End Page
P89
DOI
10.1186/2046-2530-4-S1-P89

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

Authors
Balasubramanian, R; Choi, J-H; Francescatto, L; Willer, J; Horton, ER; Asimacopoulos, EP; Stankovic, KM; Plummer, L; Buck, CL; Quinton, R; Nebesio, TD; Mericq, V; Merino, PM; Meyer, BF; Monies, D; Gusella, JF; Al Tassan, N; Katsanis, N; Crowley, WF
MLA Citation
Balasubramanian, R, Choi, J-H, Francescatto, L, Willer, J, Horton, ER, Asimacopoulos, EP, Stankovic, KM, Plummer, L, Buck, CL, Quinton, R, Nebesio, TD, Mericq, V, Merino, PM, Meyer, BF, Monies, D, Gusella, JF, Al Tassan, N, Katsanis, N, and Crowley, WF. "Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency." Proceedings of the National Academy of Sciences of the United States of America 111.50 (December 3, 2014): 17953-17958.
PMID
25472840
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
50
Publish Date
2014
Start Page
17953
End Page
17958
DOI
10.1073/pnas.1417438111

Dissecting intraflagellar transport, one molecule at a time.

Intraflagellar transport (IFT) is required for proper function of cilia, although many of the mechanistic details underlying this process are obscure. Two studies in this issue of Developmental Cell illuminate key functions of one IFT protein, IFT27, and offer clues into how IFT cargo is selected and transported.

Authors
Davis, EE; Katsanis, N
MLA Citation
Davis, EE, and Katsanis, N. "Dissecting intraflagellar transport, one molecule at a time." Developmental cell 31.3 (November 10, 2014): 263-264.
PMID
25453827
Source
epmc
Published In
Developmental Cell
Volume
31
Issue
3
Publish Date
2014
Start Page
263
End Page
264
DOI
10.1016/j.devcel.2014.10.021

Dissecting intraflagellar transport, one molecule at a time

Copyright © 2014 Elsevier Inc. All rights reserved.Intraflagellar transport (IFT) is required for proper function of cilia, although many of the mechanistic details underlying this process are obscure. Two studies in this issue of Developmental Cell illuminate key functions of one IFT protein, IFT27, and offer clues into how IFT cargo is selected and transported.

Authors
Davis, EE
MLA Citation
Davis, EE. "Dissecting intraflagellar transport, one molecule at a time." Developmental cell 31.3 (November 10, 2014): 263-264.
Source
scopus
Published In
Developmental Cell
Volume
31
Issue
3
Publish Date
2014
Start Page
263
End Page
264
DOI
10.1016/j.devcel.2014.10.021

Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.

The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

Authors
Carvalho, CMB; Vasanth, S; Shinawi, M; Russell, C; Ramocki, MB; Brown, CW; Graakjaer, J; Skytte, A-B; Vianna-Morgante, AM; Krepischi, ACV; Patel, GS; Immken, L; Aleck, K; Lim, C; Cheung, SW; Rosenberg, C; Katsanis, N; Lupski, JR
MLA Citation
Carvalho, CMB, Vasanth, S, Shinawi, M, Russell, C, Ramocki, MB, Brown, CW, Graakjaer, J, Skytte, A-B, Vianna-Morgante, AM, Krepischi, ACV, Patel, GS, Immken, L, Aleck, K, Lim, C, Cheung, SW, Rosenberg, C, Katsanis, N, and Lupski, JR. "Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes." American journal of human genetics 95.5 (November 6, 2014): 565-578.
PMID
25439725
Source
epmc
Published In
The American Journal of Human Genetics
Volume
95
Issue
5
Publish Date
2014
Start Page
565
End Page
578
DOI
10.1016/j.ajhg.2014.10.006

A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity.

Rare-variant association studies in common, complex diseases are customarily conducted under an additive risk model in both single-variant and burden testing. Here, we describe a method to improve detection of rare recessive variants in complex diseases termed RAFT (recessive-allele-frequency-based test). We found that RAFT outperforms existing approaches when the variant influences disease risk in a recessive manner on simulated data. We then applied our method to 1,791 Finnish individuals with type 2 diabetes (T2D) and 2,657 matched control subjects. In BBS10, we discovered a rare variant (c.1189A>G [p.Ile397Val]; rs202042386) that confers risk of T2D in a recessive state (p = 1.38 × 10(-6)) and would be missed by conventional methods. Testing of this variant in an established in vivo zebrafish model confirmed the variant to be pathogenic. Taken together, these data suggest that RAFT can effectively reveal rare recessive contributions to complex diseases overlooked by conventional association tests.

Authors
Lim, ET; Liu, YP; Chan, Y; Tiinamaija, T; Käräjämäki, A; Madsen, E; Altshuler, DM; Raychaudhuri, S; Groop, L; Flannick, J; Hirschhorn, JN; Katsanis, N; Daly, MJ
MLA Citation
Lim, ET, Liu, YP, Chan, Y, Tiinamaija, T, Käräjämäki, A, Madsen, E, Altshuler, DM, Raychaudhuri, S, Groop, L, Flannick, J, Hirschhorn, JN, Katsanis, N, and Daly, MJ. "A novel test for recessive contributions to complex diseases implicates Bardet-Biedl syndrome gene BBS10 in idiopathic type 2 diabetes and obesity." American journal of human genetics 95.5 (November 2014): 509-520.
PMID
25439097
Source
epmc
Published In
The American Journal of Human Genetics
Volume
95
Issue
5
Publish Date
2014
Start Page
509
End Page
520
DOI
10.1016/j.ajhg.2014.09.015

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.

Authors
Sugathan, A; Biagioli, M; Golzio, C; Erdin, S; Blumenthal, I; Manavalan, P; Ragavendran, A; Brand, H; Lucente, D; Miles, J; Sheridan, SD; Stortchevoi, A; Kellis, M; Haggarty, SJ; Katsanis, N; Gusella, JF; Talkowski, ME
MLA Citation
Sugathan, A, Biagioli, M, Golzio, C, Erdin, S, Blumenthal, I, Manavalan, P, Ragavendran, A, Brand, H, Lucente, D, Miles, J, Sheridan, SD, Stortchevoi, A, Kellis, M, Haggarty, SJ, Katsanis, N, Gusella, JF, and Talkowski, ME. "CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors." Proceedings of the National Academy of Sciences of the United States of America 111.42 (October 7, 2014): E4468-E4477.
PMID
25294932
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
42
Publish Date
2014
Start Page
E4468
End Page
E4477
DOI
10.1073/pnas.1405266111

Interpreting human genetic variation with in vivo zebrafish assays

© 2014 Elsevier B.V..Rapid advances and cost erosion in exome and genome analysis of patients with both rare and common genetic disorders have accelerated gene discovery and illuminated fundamental biological mechanisms. The thrill of discovery has been accompanied, however, with the sobering appreciation that human genomes are burdened with a large number of rare and ultra rare variants, thereby posing a significant challenge in dissecting both the effect of such alleles on protein function and also the biological relevance of these events to patient pathology. In an effort to develop model systems that are able to generate surrogates of human pathologies, a powerful suite of tools have been developed in zebrafish, taking advantage of the relatively small (compared to invertebrate models) evolutionary distance of that genome to humans, the orthology of several organs and signaling processes, and the suitability of this organism for medium and high throughput phenotypic screening. Here we will review the use of this model organism in dissecting human genetic disorders; we will highlight how diverse strategies have informed disease causality and genetic architecture; and we will discuss relative strengths and limitations of these approaches in the context of medical genome sequencing. This article is part of a Special Issue entitled: From Genome to Function.

Authors
Davis, EE; Frangakis, S; Katsanis, N
MLA Citation
Davis, EE, Frangakis, S, and Katsanis, N. "Interpreting human genetic variation with in vivo zebrafish assays." Biochimica et Biophysica Acta - Molecular Basis of Disease 1842.10 (October 1, 2014): 1960-1970. (Review)
Source
scopus
Published In
BBA - Molecular Basis of Disease
Volume
1842
Issue
10
Publish Date
2014
Start Page
1960
End Page
1970
DOI
10.1016/j.bbadis.2014.05.024

Interpreting human genetic variation with in vivo zebrafish assays.

Rapid advances and cost erosion in exome and genome analysis of patients with both rare and common genetic disorders have accelerated gene discovery and illuminated fundamental biological mechanisms. The thrill of discovery has been accompanied, however, with the sobering appreciation that human genomes are burdened with a large number of rare and ultra rare variants, thereby posing a significant challenge in dissecting both the effect of such alleles on protein function and also the biological relevance of these events to patient pathology. In an effort to develop model systems that are able to generate surrogates of human pathologies, a powerful suite of tools have been developed in zebrafish, taking advantage of the relatively small (compared to invertebrate models) evolutionary distance of that genome to humans, the orthology of several organs and signaling processes, and the suitability of this organism for medium and high throughput phenotypic screening. Here we will review the use of this model organism in dissecting human genetic disorders; we will highlight how diverse strategies have informed disease causality and genetic architecture; and we will discuss relative strengths and limitations of these approaches in the context of medical genome sequencing. This article is part of a Special Issue entitled: From Genome to Function.

Authors
Davis, EE; Frangakis, S; Katsanis, N
MLA Citation
Davis, EE, Frangakis, S, and Katsanis, N. "Interpreting human genetic variation with in vivo zebrafish assays." Biochimica et biophysica acta 1842.10 (October 2014): 1960-1970. (Review)
PMID
24887202
Source
epmc
Published In
Biochimica et Biophysica Acta: international journal of biochemistry and biophysics
Volume
1842
Issue
10
Publish Date
2014
Start Page
1960
End Page
1970
DOI
10.1016/j.bbadis.2014.05.024

A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans.

Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function.

Authors
Brooks, SS; Wall, AL; Golzio, C; Reid, DW; Kondyles, A; Willer, JR; Botti, C; Nicchitta, CV; Katsanis, N; Davis, EE
MLA Citation
Brooks, SS, Wall, AL, Golzio, C, Reid, DW, Kondyles, A, Willer, JR, Botti, C, Nicchitta, CV, Katsanis, N, and Davis, EE. "A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans." Genetics 198.2 (October 2014): 723-733.
PMID
25316788
Source
epmc
Published In
Genetics
Volume
198
Issue
2
Publish Date
2014
Start Page
723
End Page
733
DOI
10.1534/genetics.114.168211

Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Authors
Bernier, R; Golzio, C; Xiong, B; Stessman, HA; Coe, BP; Penn, O; Witherspoon, K; Gerdts, J; Baker, C; Vulto-van Silfhout, AT; Schuurs-Hoeijmakers, JH; Fichera, M; Bosco, P; Buono, S; Alberti, A; Failla, P; Peeters, H; Steyaert, J; Vissers, LELM; Francescatto, L; Mefford, HC; Rosenfeld, JA; Bakken, T; O'Roak, BJ; Pawlus, M; Moon, R; Shendure, J; Amaral, DG; Lein, E; Rankin, J; Romano, C; de Vries, BBA; Katsanis, N; Eichler, EE
MLA Citation
Bernier, R, Golzio, C, Xiong, B, Stessman, HA, Coe, BP, Penn, O, Witherspoon, K, Gerdts, J, Baker, C, Vulto-van Silfhout, AT, Schuurs-Hoeijmakers, JH, Fichera, M, Bosco, P, Buono, S, Alberti, A, Failla, P, Peeters, H, Steyaert, J, Vissers, LELM, Francescatto, L, Mefford, HC, Rosenfeld, JA, Bakken, T, O'Roak, BJ, Pawlus, M, Moon, R, Shendure, J, Amaral, DG, Lein, E, Rankin, J, Romano, C, de Vries, BBA, Katsanis, N, and Eichler, EE. "Disruptive CHD8 mutations define a subtype of autism early in development." Cell 158.2 (July 3, 2014): 263-276.
PMID
24998929
Source
epmc
Published In
Cell
Volume
158
Issue
2
Publish Date
2014
Start Page
263
End Page
276
DOI
10.1016/j.cell.2014.06.017

A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype.

Loss-of-function mutations in PAK3 contribute to non-syndromic X-linked intellectual disability (NS-XLID) by affecting dendritic spine density and morphology. Linkage analysis in a three-generation family with affected males showing ID, agenesis of corpus callosum, cerebellar hypoplasia, microcephaly and ichthyosis, revealed a candidate disease locus in Xq21.33q24 encompassing over 280 genes. Subsequent to sequencing all coding exons of the X chromosome, we identified a single novel variant within the linkage region, affecting a conserved codon of PAK3. Biochemical studies showed that, similar to previous NS-XLID-associated lesions, the predicted amino acid substitution (Lys389Asn) abolished the kinase activity of PAK3. In addition, the introduced residue conferred a dominant-negative function to the protein that drives the syndromic phenotype. Using a combination of in vitro and in vivo studies in zebrafish embryos, we show that PAK3(N389) escapes its physiologic degradation and is able to perturb MAPK signaling via an uncontrolled kinase-independent function, which in turn leads to alterations of cerebral and craniofacial structures in vivo. Our data expand the spectrum of phenotypes associated with PAK3 mutations, characterize a novel mechanism resulting in a dual molecular effect of the same mutation with a complex PAK3 functional deregulation and provide evidence for a direct functional impact of aberrant PAK3 function on MAPK signaling.

Authors
Magini, P; Pippucci, T; Tsai, I-C; Coppola, S; Stellacci, E; Bartoletti-Stella, A; Turchetti, D; Graziano, C; Cenacchi, G; Neri, I; Cordelli, DM; Marchiani, V; Bergamaschi, R; Gasparre, G; Neri, G; Mazzanti, L; Patrizi, A; Franzoni, E; Romeo, G; Bordo, D; Tartaglia, M; Katsanis, N; Seri, M
MLA Citation
Magini, P, Pippucci, T, Tsai, I-C, Coppola, S, Stellacci, E, Bartoletti-Stella, A, Turchetti, D, Graziano, C, Cenacchi, G, Neri, I, Cordelli, DM, Marchiani, V, Bergamaschi, R, Gasparre, G, Neri, G, Mazzanti, L, Patrizi, A, Franzoni, E, Romeo, G, Bordo, D, Tartaglia, M, Katsanis, N, and Seri, M. "A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype." Human molecular genetics 23.13 (July 2014): 3607-3617.
PMID
24556213
Source
epmc
Published In
Human Molecular Genetics
Volume
23
Issue
13
Publish Date
2014
Start Page
3607
End Page
3617
DOI
10.1093/hmg/ddu070

Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established in vivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by in vivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.

Authors
Schulte, EC; Kousi, M; Tan, PL; Tilch, E; Knauf, F; Lichtner, P; Trenkwalder, C; Högl, B; Frauscher, B; Berger, K; Fietze, I; Hornyak, M; Oertel, WH; Bachmann, CG; Zimprich, A; Peters, A; Gieger, C; Meitinger, T; Müller-Myhsok, B; Katsanis, N; Winkelmann, J
MLA Citation
Schulte, EC, Kousi, M, Tan, PL, Tilch, E, Knauf, F, Lichtner, P, Trenkwalder, C, Högl, B, Frauscher, B, Berger, K, Fietze, I, Hornyak, M, Oertel, WH, Bachmann, CG, Zimprich, A, Peters, A, Gieger, C, Meitinger, T, Müller-Myhsok, B, Katsanis, N, and Winkelmann, J. "Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome." American journal of human genetics 95.1 (July 2014): 85-95.
PMID
24995868
Source
epmc
Published In
The American Journal of Human Genetics
Volume
95
Issue
1
Publish Date
2014
Start Page
85
End Page
95
DOI
10.1016/j.ajhg.2014.06.005

Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development

Authors
Bernier, R; Golzio, C; Xiong, B; Stessman, HA; Coe, BP; Penn, O; Witherspoon, K; Gerdts, J; Baker, C; Vulto-van Silfhout, AT; Schuurs-Hoeijmakers, JH; Fichera, M; Bosco, P; Buono, S; Alberti, A; Failla, P; Peeters, H; Steyaert, J; Vissers, LELM; Francescatto, L; Mefford, HC; Rosenfeld, JA; Bakken, T; O’Roak, BJ; Pawlus, M; Moon, R; Shendure, J; Amaral, DG; Lein, E; Rankin, J; Romano, C; de Vries, BBA; Katsanis, N; Eichler, EE
MLA Citation
Bernier, R, Golzio, C, Xiong, B, Stessman, HA, Coe, BP, Penn, O, Witherspoon, K, Gerdts, J, Baker, C, Vulto-van Silfhout, AT, Schuurs-Hoeijmakers, JH, Fichera, M, Bosco, P, Buono, S, Alberti, A, Failla, P, Peeters, H, Steyaert, J, Vissers, LELM, Francescatto, L, Mefford, HC, Rosenfeld, JA, Bakken, T, O’Roak, BJ, Pawlus, M, Moon, R, Shendure, J, Amaral, DG, Lein, E, Rankin, J, Romano, C, de Vries, BBA, Katsanis, N, and Eichler, EE. "Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development." Cell 158.2 (July 2014): 263-276.
Source
crossref
Published In
Cell
Volume
158
Issue
2
Publish Date
2014
Start Page
263
End Page
276
DOI
10.1016/j.cell.2014.06.017

Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome

Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder. © 2014 The American Society of Human Genetics.

Authors
Lindstrand, A; Davis, EE; Carvalho, CMB; Pehlivan, D; Willer, JR; Tsai, IC; Ramanathan, S; Zuppan, C; Sabo, A; Muzny, D; Gibbs, R; Liu, P; Lewis, RA; Banin, E; Lupski, JR; Clark, R; Katsanis, N
MLA Citation
Lindstrand, A, Davis, EE, Carvalho, CMB, Pehlivan, D, Willer, JR, Tsai, IC, Ramanathan, S, Zuppan, C, Sabo, A, Muzny, D, Gibbs, R, Liu, P, Lewis, RA, Banin, E, Lupski, JR, Clark, R, and Katsanis, N. "Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome." American Journal of Human Genetics 94.5 (May 1, 2014): 745-754.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
94
Issue
5
Publish Date
2014
Start Page
745
End Page
754
DOI
10.1016/j.ajhg.2014.03.017

Elution profile analysis of SDS-induced subcomplexes by quantitative mass spectrometry.

Analyzing the molecular architecture of native multiprotein complexes via biochemical methods has so far been difficult and error prone. Protein complex isolation by affinity purification can define the protein repertoire of a given complex, yet, it remains difficult to gain knowledge of its substructure or modular composition. Here, we introduce SDS concentration gradient induced decomposition of protein complexes coupled to quantitative mass spectrometry and in silico elution profile distance analysis. By applying this new method to a cellular transport module, the IFT/lebercilin complex, we demonstrate its ability to determine modular composition as well as sensitively detect known and novel complex components. We show that the IFT/lebercilin complex can be separated into at least five submodules, the IFT complex A, the IFT complex B, the 14-3-3 protein complex and the CTLH complex, as well as the dynein light chain complex. Furthermore, we identify the protein TULP3 as a potential new member of the IFT complex A and showed that several proteins, classified as IFT complex B-associated, are integral parts of this complex. To further demonstrate EPASIS general applicability, we analyzed the modular substructure of two additional complexes, that of B-RAF and of 14-3-3-ε. The results show, that EPASIS provides a robust as well as sensitive strategy to dissect the substructure of large multiprotein complexes in a highly time- as well as cost-effective manner.

Authors
Texier, Y; Toedt, G; Gorza, M; Mans, DA; van Reeuwijk, J; Horn, N; Willer, J; Katsanis, N; Roepman, R; Gibson, TJ; Ueffing, M; Boldt, K
MLA Citation
Texier, Y, Toedt, G, Gorza, M, Mans, DA, van Reeuwijk, J, Horn, N, Willer, J, Katsanis, N, Roepman, R, Gibson, TJ, Ueffing, M, and Boldt, K. "Elution profile analysis of SDS-induced subcomplexes by quantitative mass spectrometry." Molecular & cellular proteomics : MCP 13.5 (May 2014): 1382-1391.
PMID
24563533
Source
epmc
Published In
Molecular & cellular proteomics : MCP
Volume
13
Issue
5
Publish Date
2014
Start Page
1382
End Page
1391
DOI
10.1074/mcp.o113.033233

Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators.

Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients.

Authors
Liu, YP; Tsai, I-C; Morleo, M; Oh, EC; Leitch, CC; Massa, F; Lee, B-H; Parker, DS; Finley, D; Zaghloul, NA; Franco, B; Katsanis, N
MLA Citation
Liu, YP, Tsai, I-C, Morleo, M, Oh, EC, Leitch, CC, Massa, F, Lee, B-H, Parker, DS, Finley, D, Zaghloul, NA, Franco, B, and Katsanis, N. "Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators." The Journal of clinical investigation 124.5 (May 2014): 2059-2070.
PMID
24691443
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
5
Publish Date
2014
Start Page
2059
End Page
2070
DOI
10.1172/jci71898

Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome.

Homozygosity for a recurrent 290 kb deletion of NPHP1 is the most frequent cause of isolated nephronophthisis (NPHP) in humans. A deletion of the same genomic interval has also been detected in individuals with Joubert syndrome (JBTS), and in the mouse, Nphp1 interacts genetically with Ahi1, a known JBTS locus. Given these observations, we investigated the contribution of NPHP1 in Bardet-Biedl syndrome (BBS), a ciliopathy of intermediate severity. By using a combination of array-comparative genomic hybridization, TaqMan copy number assays, and sequencing, we studied 200 families affected by BBS. We report a homozygous NPHP1 deletion CNV in a family with classical BBS that is transmitted with autosomal-recessive inheritance. Further, we identified heterozygous NPHP1 deletions in two more unrelated persons with BBS who bear primary mutations at another BBS locus. In parallel, we identified five families harboring an SNV in NPHP1 resulting in a conserved missense change, c.14G>T (p.Arg5Leu), that is enriched in our Hispanic pedigrees; in each case, affected individuals carried additional bona fide pathogenic alleles in another BBS gene. In vivo functional modeling in zebrafish embryos demonstrated that c.14G>T is a loss-of-function variant, and suppression of nphp1 in concert with each of the primary BBS loci found in our NPHP1-positive pedigrees exacerbated the severity of the phenotype. These results suggest that NPHP1 mutations are probably rare primary causes of BBS that contribute to the mutational burden of the disorder.

Authors
Lindstrand, A; Davis, EE; Carvalho, CMB; Pehlivan, D; Willer, JR; Tsai, I-C; Ramanathan, S; Zuppan, C; Sabo, A; Muzny, D; Gibbs, R; Liu, P; Lewis, RA; Banin, E; Lupski, JR; Clark, R; Katsanis, N
MLA Citation
Lindstrand, A, Davis, EE, Carvalho, CMB, Pehlivan, D, Willer, JR, Tsai, I-C, Ramanathan, S, Zuppan, C, Sabo, A, Muzny, D, Gibbs, R, Liu, P, Lewis, RA, Banin, E, Lupski, JR, Clark, R, and Katsanis, N. "Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome." American journal of human genetics 94.5 (May 2014): 745-754.
PMID
24746959
Source
epmc
Published In
The American Journal of Human Genetics
Volume
94
Issue
5
Publish Date
2014
Start Page
745
End Page
754
DOI
10.1016/j.ajhg.2014.03.017

Whole exome sequencing of a dominant retinitis pigmentosa family identifies a novel deletion in PRPF31.

Mutations at some retinitis pigmentosa (RP) loci are associated with variable penetrance and expressivity, exacerbating diagnostic challenges. The purpose of this study was to dissect the genetic underpinnings of nonsyndromic RP with variable age of onset in a large Mexican family.We ascertained members of a large, multigenerational pedigree using a complete ophthalmic examination. We performed whole exome sequencing on two affected first cousins, an obligate carrier, and a married-in spouse. Confirmatory sequencing of candidate variants was performed in the entire pedigree, as well as genotyping and mRNA studies to investigate expression changes in the causal locus.We identified a 14-base pair (bp) deletion in PRPF31, a gene implicated previously in autosomal dominant (ad) RP. The mutation segregated with the phenotype of all 10 affected females, but also was present in six asymptomatics (two females and four males). Studies in patient cells showed that the penetrance/expressivity of the PRPF31 deletion allele was concordant with the expression levels of wild-type message. However, neither the known PRPF31 modulators nor cis-eQTLs within 1 Mb of the locus could account for the variable expression of message or the clinical phenotype.We have identified a novel 14-bp deletion in PRPF31 as the genetic driver of adRP in a large Mexican family that exhibits nonpenetrance and variable expressivity, known properties of this locus. However, our studies intimate the presence of additional loci that can modify PRPF31 expression.

Authors
Villanueva, A; Willer, JR; Bryois, J; Dermitzakis, ET; Katsanis, N; Davis, EE
MLA Citation
Villanueva, A, Willer, JR, Bryois, J, Dermitzakis, ET, Katsanis, N, and Davis, EE. "Whole exome sequencing of a dominant retinitis pigmentosa family identifies a novel deletion in PRPF31." Investigative ophthalmology & visual science 55.4 (April 7, 2014): 2121-2129.
PMID
24595387
Source
epmc
Published In
Investigative Ophthalmology and Visual Science
Volume
55
Issue
4
Publish Date
2014
Start Page
2121
End Page
2129
DOI
10.1167/iovs.13-13827

Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT

Skeletal dysplasias are challenging to diagnose because of their phenotypic variability, genetic heterogeneity, and diverse inheritance patterns. We conducted whole exome sequencing of a Turkish male with a suspected X-linked skeletal dysplasia of unknown etiology as well as his unaffected mother and maternal uncle. Bioinformatic filtering of variants implicated in skeletal system development revealed a novel hemizygous mutation, c.341-(11_9)delAAT, in an intron of TRAPPC2, the causative locus of spondyloepiphyseal dysplasia tarda (SEDT). We show that this deletion leads to the loss of wild-type TRAPPC2 and the generation of two functionally impaired mRNAs in patient cells. These consequences are predicted to disrupt function of SEDLIN/TRAPPC2. The clinical and research data were returned, with appropriate caveats, to the patient and informed his disease status and reproductive choices. Our findings expand the allelic repertoire of SEDT and show how prior filtering of the morbid human genome informed by inheritance pattern and phenotype, when combined with appropriate functional tests in patient-derived cells, can expedite discovery, overcome issues of missing data and help interpret variants of unknown significance. Finally, this example shows how the return of a clinically confirmed mutational finding, supported by research allele pathogenicity data, can assist individuals with inherited disorders with life choices. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Authors
Davis, EE; Savage, JH; Willer, JR; Jiang, YH; Angrist, M; Androutsopoulos, A; Katsanis, N
MLA Citation
Davis, EE, Savage, JH, Willer, JR, Jiang, YH, Angrist, M, Androutsopoulos, A, and Katsanis, N. "Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT." Clinical Genetics 85.4 (April 1, 2014): 359-364.
Source
scopus
Published In
Clinical Genetics
Volume
85
Issue
4
Publish Date
2014
Start Page
359
End Page
364
DOI
10.1111/cge.12189

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

Authors
Gee, HY; Otto, EA; Hurd, TW; Ashraf, S; Chaki, M; Cluckey, A; Vega-Warner, V; Saisawat, P; Diaz, KA; Fang, H; Kohl, S; Allen, SJ; Airik, R; Zhou, W; Ramaswami, G; Janssen, S; Fu, C; Innis, JL; Weber, S; Vester, U; Davis, EE; Katsanis, N; Fathy, HM; Jeck, N; Klaus, G; Nayir, A; Rahim, KA; Al Attrach, I; Al Hassoun, I; Ozturk, S; Drozdz, D; Helmchen, U; O'Toole, JF; Attanasio, M; Lewis, RA; Nürnberg, G; Nürnberg, P; Washburn, J; MacDonald, J; Innis, JW; Levy, S; Hildebrandt, F
MLA Citation
Gee, HY, Otto, EA, Hurd, TW, Ashraf, S, Chaki, M, Cluckey, A, Vega-Warner, V, Saisawat, P, Diaz, KA, Fang, H, Kohl, S, Allen, SJ, Airik, R, Zhou, W, Ramaswami, G, Janssen, S, Fu, C, Innis, JL, Weber, S, Vester, U, Davis, EE, Katsanis, N, Fathy, HM, Jeck, N, Klaus, G, Nayir, A, Rahim, KA, Al Attrach, I, Al Hassoun, I, Ozturk, S, Drozdz, D, Helmchen, U, O'Toole, JF, Attanasio, M, Lewis, RA, Nürnberg, G, Nürnberg, P, Washburn, J, MacDonald, J, Innis, JW, Levy, S, and Hildebrandt, F. "Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies." Kidney Int 85.4 (April 2014): 880-887.
PMID
24257694
Source
pubmed
Published In
Kidney international
Volume
85
Issue
4
Publish Date
2014
Start Page
880
End Page
887
DOI
10.1038/ki.2013.450

Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT.

Skeletal dysplasias are challenging to diagnose because of their phenotypic variability, genetic heterogeneity, and diverse inheritance patterns. We conducted whole exome sequencing of a Turkish male with a suspected X-linked skeletal dysplasia of unknown etiology as well as his unaffected mother and maternal uncle. Bioinformatic filtering of variants implicated in skeletal system development revealed a novel hemizygous mutation, c.341-(11_9)delAAT, in an intron of TRAPPC2, the causative locus of spondyloepiphyseal dysplasia tarda (SEDT). We show that this deletion leads to the loss of wild-type TRAPPC2 and the generation of two functionally impaired mRNAs in patient cells. These consequences are predicted to disrupt function of SEDLIN/TRAPPC2. The clinical and research data were returned, with appropriate caveats, to the patient and informed his disease status and reproductive choices. Our findings expand the allelic repertoire of SEDT and show how prior filtering of the morbid human genome informed by inheritance pattern and phenotype, when combined with appropriate functional tests in patient-derived cells, can expedite discovery, overcome issues of missing data and help interpret variants of unknown significance. Finally, this example shows how the return of a clinically confirmed mutational finding, supported by research allele pathogenicity data, can assist individuals with inherited disorders with life choices.

Authors
Davis, EE; Savage, JH; Willer, JR; Jiang, Y-H; Angrist, M; Androutsopoulos, A; Katsanis, N
MLA Citation
Davis, EE, Savage, JH, Willer, JR, Jiang, Y-H, Angrist, M, Androutsopoulos, A, and Katsanis, N. "Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT." Clin Genet 85.4 (April 2014): 359-364.
PMID
23656395
Source
pubmed
Published In
Clinical Genetics
Volume
85
Issue
4
Publish Date
2014
Start Page
359
End Page
364
DOI
10.1111/cge.12189

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis.

Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.

Authors
Nesin, V; Wiley, G; Kousi, M; Ong, E-C; Lehmann, T; Nicholl, DJ; Suri, M; Shahrizaila, N; Katsanis, N; Gaffney, PM; Wierenga, KJ; Tsiokas, L
MLA Citation
Nesin, V, Wiley, G, Kousi, M, Ong, E-C, Lehmann, T, Nicholl, DJ, Suri, M, Shahrizaila, N, Katsanis, N, Gaffney, PM, Wierenga, KJ, and Tsiokas, L. "Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis." Proceedings of the National Academy of Sciences of the United States of America 111.11 (March 3, 2014): 4197-4202.
PMID
24591628
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
111
Issue
11
Publish Date
2014
Start Page
4197
End Page
4202
DOI
10.1073/pnas.1312520111

Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development.

The bone morphogenetic protein (BMP) signaling pathways have important roles in embryonic development and cellular homeostasis, with aberrant BMP signaling resulting in a broad spectrum of human disease. We report that BMPs unexpectedly signal through the canonical transforming growth factor β (TGF-β)-responsive Smad2 and Smad3. BMP-induced Smad2/3 signaling occurs preferentially in embryonic cells and transformed cells. BMPs signal to Smad2/3 by stimulating complex formation between the BMP-binding TGF-β superfamily receptors, activin receptor-like kinase (ALK)3/6, and the Smad2/3 phosphorylating receptors ALK5/7. BMP signaling through Smad2 mediates, in part, dorsoventral axis patterning in zebrafish embryos, whereas BMP signaling through Smad3 facilitates cancer cell invasion. Consistent with increased BMP-mediated Smad2/3 signaling during cancer progression, Smad1/5 and Smad 2/3 signaling converge in human cancer specimens. Thus, the signaling mechanisms used by BMPs and TGF-β superfamily receptors are broader than previously appreciated.

Authors
Holtzhausen, A; Golzio, C; How, T; Lee, Y-H; Schiemann, WP; Katsanis, N; Blobe, GC
MLA Citation
Holtzhausen, A, Golzio, C, How, T, Lee, Y-H, Schiemann, WP, Katsanis, N, and Blobe, GC. "Novel bone morphogenetic protein signaling through Smad2 and Smad3 to regulate cancer progression and development." FASEB J 28.3 (March 2014): 1248-1267.
PMID
24308972
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
28
Issue
3
Publish Date
2014
Start Page
1248
End Page
1267
DOI
10.1096/fj.13-239178

Managing incidental genomic findings in clinical trials: fulfillment of the principle of justice.

Authors
Dal-Ré, R; Katsanis, N; Katsanis, S; Parker, LS; Ayuso, C
MLA Citation
Dal-Ré, R, Katsanis, N, Katsanis, S, Parker, LS, and Ayuso, C. "Managing incidental genomic findings in clinical trials: fulfillment of the principle of justice." PLoS medicine 11.1 (January 14, 2014): e1001584-.
PMID
24453945
Source
epmc
Published In
PLoS medicine
Volume
11
Issue
1
Publish Date
2014
Start Page
e1001584
DOI
10.1371/journal.pmed.1001584

Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans.

Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syndrome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedgehog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies.

Authors
Shaheen, R; Shamseldin, HE; Loucks, CM; Seidahmed, MZ; Ansari, S; Ibrahim Khalil, M; Al-Yacoub, N; Davis, EE; Mola, NA; Szymanska, K; Herridge, W; Chudley, AE; Chodirker, BN; Schwartzentruber, J; Majewski, J; Katsanis, N; Poizat, C; Johnson, CA; Parboosingh, J; Boycott, KM; Innes, AM; Alkuraya, FS
MLA Citation
Shaheen, R, Shamseldin, HE, Loucks, CM, Seidahmed, MZ, Ansari, S, Ibrahim Khalil, M, Al-Yacoub, N, Davis, EE, Mola, NA, Szymanska, K, Herridge, W, Chudley, AE, Chodirker, BN, Schwartzentruber, J, Majewski, J, Katsanis, N, Poizat, C, Johnson, CA, Parboosingh, J, Boycott, KM, Innes, AM, and Alkuraya, FS. "Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans." Am J Hum Genet 94.1 (January 2, 2014): 73-79.
PMID
24360803
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
94
Issue
1
Publish Date
2014
Start Page
73
End Page
79
DOI
10.1016/j.ajhg.2013.11.010

Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans

Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syndrome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedgehog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies. © 2014 The American Society of Human Genetics.

Authors
Shaheen, R; Shamseldin, HE; Loucks, CM; Seidahmed, MZ; Ansari, S; Ibrahim Khalil, M; Al-Yacoub, N; Davis, EE; Mola, NA; Szymanska, K; Herridge, W; Chudley, AE; Chodirker, BN; Schwartzentruber, J; Majewski, J; Katsanis, N; Poizat, C; Johnson, CA; Parboosingh, J; Boycott, KM; Innes, AM; Alkuraya, FS
MLA Citation
Shaheen, R, Shamseldin, HE, Loucks, CM, Seidahmed, MZ, Ansari, S, Ibrahim Khalil, M, Al-Yacoub, N, Davis, EE, Mola, NA, Szymanska, K, Herridge, W, Chudley, AE, Chodirker, BN, Schwartzentruber, J, Majewski, J, Katsanis, N, Poizat, C, Johnson, CA, Parboosingh, J, Boycott, KM, Innes, AM, and Alkuraya, FS. "Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans." American Journal of Human Genetics 94.1 (January 2, 2014): 73-79.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
94
Issue
1
Publish Date
2014
Start Page
73
End Page
79
DOI
10.1016/j.ajhg.2013.11.010

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms. © 2013 International Society of Nephrology.

Authors
Gee, HY; Otto, EA; Hurd, TW; Ashraf, S; Chaki, M; Cluckey, A; Vega-Warner, V; Saisawat, P; Diaz, KA; Fang, H; Kohl, S; Allen, SJ; Airik, R; Zhou, W; Ramaswami, G; Janssen, S; Fu, C; Innis, JL; Weber, S; Vester, U; Davis, EE; Katsanis, N; Fathy, HM; Jeck, N; Klaus, G; Nayir, A; Rahim, KA; Attrach, IA; Hassoun, IA; Ozturk, S; Drozdz, D; Helmchen, U; O'toole, JF; Attanasio, M; Lewis, RA; Nürnberg, G; Nürnberg, P; Washburn, J; Macdonald, J; Innis, JW; Levy, S; Hildebrandt, F
MLA Citation
Gee, HY, Otto, EA, Hurd, TW, Ashraf, S, Chaki, M, Cluckey, A, Vega-Warner, V, Saisawat, P, Diaz, KA, Fang, H, Kohl, S, Allen, SJ, Airik, R, Zhou, W, Ramaswami, G, Janssen, S, Fu, C, Innis, JL, Weber, S, Vester, U, Davis, EE, Katsanis, N, Fathy, HM, Jeck, N, Klaus, G, Nayir, A, Rahim, KA, Attrach, IA, Hassoun, IA, Ozturk, S, Drozdz, D, Helmchen, U, O'toole, JF, Attanasio, M, Lewis, RA, Nürnberg, G, Nürnberg, P, Washburn, J, Macdonald, J, Innis, JW, Levy, S, and Hildebrandt, F. "Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies." Kidney International 85.4 (January 1, 2014): 880-887.
Source
scopus
Published In
Kidney international
Volume
85
Issue
4
Publish Date
2014
Start Page
880
End Page
887
DOI
10.1038/ki.2013.450

Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

Authors
Carnes, MU; Liu, YP; Allingham, RR; Whigham, BT; Havens, S; Garrett, ME; Qiao, C; Katsanis, N; Wiggs, JL; Pasquale, LR; Ashley-Koch, A; Oh, EC; Hauser, MA
MLA Citation
Carnes, MU, Liu, YP, Allingham, RR, Whigham, BT, Havens, S, Garrett, ME, Qiao, C, Katsanis, N, Wiggs, JL, Pasquale, LR, Ashley-Koch, A, Oh, EC, and Hauser, MA. "Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma." PLoS genetics 10.5 (January 2014): e1004372-.
PMID
24875647
Source
epmc
Published In
PLoS genetics
Volume
10
Issue
5
Publish Date
2014
Start Page
e1004372
DOI
10.1371/journal.pgen.1004372

Next-generation sequencing of the human olfactory receptors

Humans have approximately 400 intact olfactory receptors (ORs). Among this set there are a large number of variations between individuals, a subset of which affects receptor function and can lead to interindividual variation in olfactory perception. Technological progress and cost erosion in next-generation sequencing have given us the opportunity to determine the sequence of the entire OR gene set with high fi delity and to measure the extent of variation in this functional module across many individuals. Given that whole genome sequencing remains prohibitively expensive for this purpose, especially since the OR sub-genome represents only ~0.0125 % of the human genome, we have designed a targeted capture method to enrich the OR for next-generation sequencing, which we describe here. Using this method we have been able to sequence an individual's OR sub-genome with high coverage, enabling us to identify variation with high sensitivity and speci fi city. This method can be used to accurate assess the amount of variability in this module and to identify the functional role of individual ORs in olfactory perception. © Springer Science+Business Media, LLC 2013.

Authors
Mainland, JD; Willer, JR; Matsunami, H; Katsanis, NR
MLA Citation
Mainland, JD, Willer, JR, Matsunami, H, and Katsanis, NR. "Next-generation sequencing of the human olfactory receptors." Methods in Molecular Biology 1003 (December 1, 2013): 133-147.
Source
scopus
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1003
Publish Date
2013
Start Page
133
End Page
147
DOI
10.1007/978-1-62703-377-0-10

Defects in the IFT-B component IFT172 cause jeune and mainzer-saldino syndromes in humans

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or wholeexome resequencing in 63 individuals with ATD.We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A. © 2013 by The American Society of Human Genetics. All rights reserved.

Authors
Halbritter, J; Bizet, AA; Schmidts, M; Porath, JD; Braun, DA; Gee, HY; McInerney-Leo, AM; Krug, P; Filhol, E; Davis, EE; Airik, R; Czarnecki, PG; Lehman, AM; Trnka, P; Nitschké, P; Bole-Feysot, C; Schueler, M; Knebelmann, B; Burtey, S; Szabó, AJ; Tory, K; Leo, PJ; Gardiner, B; McKenzie, FA; Zankl, A; Brown, MA; Hartley, JL; Maher, ER; Li, C; Leroux, MR; Scambler, PJ; Zhan, SH; Jones, SJ; Kayserili, H; Tuysuz, B; Moorani, KN; Constantinescu, A; Krantz, ID; Kaplan, BS; Shah, JV; Hurd, TW et al.
MLA Citation
Halbritter, J, Bizet, AA, Schmidts, M, Porath, JD, Braun, DA, Gee, HY, McInerney-Leo, AM, Krug, P, Filhol, E, Davis, EE, Airik, R, Czarnecki, PG, Lehman, AM, Trnka, P, Nitschké, P, Bole-Feysot, C, Schueler, M, Knebelmann, B, Burtey, S, Szabó, AJ, Tory, K, Leo, PJ, Gardiner, B, McKenzie, FA, Zankl, A, Brown, MA, Hartley, JL, Maher, ER, Li, C, Leroux, MR, Scambler, PJ, Zhan, SH, Jones, SJ, Kayserili, H, Tuysuz, B, Moorani, KN, Constantinescu, A, Krantz, ID, Kaplan, BS, Shah, JV, and Hurd, TW et al. "Defects in the IFT-B component IFT172 cause jeune and mainzer-saldino syndromes in humans." American Journal of Human Genetics 93.5 (November 7, 2013): 915-925.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
93
Issue
5
Publish Date
2013
Start Page
915
End Page
925
DOI
10.1016/j.ajhg.2013.09.012

Scrib and puf60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-Number variant

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions. © 2013 by The American Society of Human Genetics. All rights reserved.

Authors
Dauber, A; Golzio, C; Guenot, C; Jodelka, FM; Kibaek, M; Kjaergaard, S; Leheup, B; Martinet, D; Nowaczyk, MJM; Rosenfeld, JA; Zeesman, S; Zunich, J; Beckmann, JS; Hirschhorn, JN; Hastings, ML; Jacquemont, S; Katsanis, N
MLA Citation
Dauber, A, Golzio, C, Guenot, C, Jodelka, FM, Kibaek, M, Kjaergaard, S, Leheup, B, Martinet, D, Nowaczyk, MJM, Rosenfeld, JA, Zeesman, S, Zunich, J, Beckmann, JS, Hirschhorn, JN, Hastings, ML, Jacquemont, S, and Katsanis, N. "Scrib and puf60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-Number variant." American Journal of Human Genetics 93.5 (November 7, 2013): 798-811.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
93
Issue
5
Publish Date
2013
Start Page
798
End Page
811
DOI
10.1016/j.ajhg.2013.09.010

Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.

Authors
Halbritter, J; Bizet, AA; Schmidts, M; Porath, JD; Braun, DA; Gee, HY; McInerney-Leo, AM; Krug, P; Filhol, E; Davis, EE; Airik, R; Czarnecki, PG; Lehman, AM; Trnka, P; Nitschké, P; Bole-Feysot, C; Schueler, M; Knebelmann, B; Burtey, S; Szabó, AJ; Tory, K; Leo, PJ; Gardiner, B; McKenzie, FA; Zankl, A; Brown, MA; Hartley, JL; Maher, ER; Li, C; Leroux, MR; Scambler, PJ; Zhan, SH; Jones, SJ; Kayserili, H; Tuysuz, B; Moorani, KN; Constantinescu, A; Krantz, ID; Kaplan, BS; Shah, JV et al.
MLA Citation
Halbritter, J, Bizet, AA, Schmidts, M, Porath, JD, Braun, DA, Gee, HY, McInerney-Leo, AM, Krug, P, Filhol, E, Davis, EE, Airik, R, Czarnecki, PG, Lehman, AM, Trnka, P, Nitschké, P, Bole-Feysot, C, Schueler, M, Knebelmann, B, Burtey, S, Szabó, AJ, Tory, K, Leo, PJ, Gardiner, B, McKenzie, FA, Zankl, A, Brown, MA, Hartley, JL, Maher, ER, Li, C, Leroux, MR, Scambler, PJ, Zhan, SH, Jones, SJ, Kayserili, H, Tuysuz, B, Moorani, KN, Constantinescu, A, Krantz, ID, Kaplan, BS, and Shah, JV et al. "Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans." Am J Hum Genet 93.5 (November 7, 2013): 915-925.
PMID
24140113
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
93
Issue
5
Publish Date
2013
Start Page
915
End Page
925
DOI
10.1016/j.ajhg.2013.09.012

SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant.

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.

Authors
Dauber, A; Golzio, C; Guenot, C; Jodelka, FM; Kibaek, M; Kjaergaard, S; Leheup, B; Martinet, D; Nowaczyk, MJM; Rosenfeld, JA; Zeesman, S; Zunich, J; Beckmann, JS; Hirschhorn, JN; Hastings, ML; Jacquemont, S; Katsanis, N
MLA Citation
Dauber, A, Golzio, C, Guenot, C, Jodelka, FM, Kibaek, M, Kjaergaard, S, Leheup, B, Martinet, D, Nowaczyk, MJM, Rosenfeld, JA, Zeesman, S, Zunich, J, Beckmann, JS, Hirschhorn, JN, Hastings, ML, Jacquemont, S, and Katsanis, N. "SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant." Am J Hum Genet 93.5 (November 7, 2013): 798-811.
PMID
24140112
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
93
Issue
5
Publish Date
2013
Start Page
798
End Page
811
DOI
10.1016/j.ajhg.2013.09.010

Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration

To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10 -8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10 -5, OR = 2.8; joint P = 5.2 × 10 -9, OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10 -5, OR = 2.2; joint P = 6.5 × 10 -7, OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder. © 2013 Nature America, Inc. All rights reserved.

Authors
Seddon, JM; Yu, Y; Miller, EC; Reynolds, R; Tan, PL; Gowrisankar, S; Goldstein, JI; Triebwasser, M; Anderson, HE; Zerbib, J; Kavanagh, D; Souied, E; Katsanis, N; Daly, MJ; Atkinson, JP; Raychaudhuri, S
MLA Citation
Seddon, JM, Yu, Y, Miller, EC, Reynolds, R, Tan, PL, Gowrisankar, S, Goldstein, JI, Triebwasser, M, Anderson, HE, Zerbib, J, Kavanagh, D, Souied, E, Katsanis, N, Daly, MJ, Atkinson, JP, and Raychaudhuri, S. "Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration." Nature Genetics 45.11 (November 1, 2013): 1366-1373. (Letter)
Source
scopus
Published In
Nature Genetics
Volume
45
Issue
11
Publish Date
2013
Start Page
1366
End Page
1373
DOI
10.1038/ng.2741

Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.

To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10(-8)). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10(-5), OR = 2.8; joint P = 5.2 × 10(-9), OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10(-5), OR = 2.2; joint P = 6.5 × 10(-7), OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.

Authors
Seddon, JM; Yu, Y; Miller, EC; Reynolds, R; Tan, PL; Gowrisankar, S; Goldstein, JI; Triebwasser, M; Anderson, HE; Zerbib, J; Kavanagh, D; Souied, E; Katsanis, N; Daly, MJ; Atkinson, JP; Raychaudhuri, S
MLA Citation
Seddon, JM, Yu, Y, Miller, EC, Reynolds, R, Tan, PL, Gowrisankar, S, Goldstein, JI, Triebwasser, M, Anderson, HE, Zerbib, J, Kavanagh, D, Souied, E, Katsanis, N, Daly, MJ, Atkinson, JP, and Raychaudhuri, S. "Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration." Nat Genet 45.11 (November 2013): 1366-1370.
PMID
24036952
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
11
Publish Date
2013
Start Page
1366
End Page
1370
DOI
10.1038/ng.2741

Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish.

Forward genetic approaches in zebrafish have provided invaluable information about developmental processes. However, the relative difficulty of mapping and isolating mutations has limited the number of new genetic screens. Recent improvements in the annotation of the zebrafish genome coupled to a reduction in sequencing costs prompted the development of whole genome and RNA sequencing approaches for gene discovery. Here we describe a whole exome sequencing (WES) approach that allows rapid and cost-effective identification of mutations. We used our WES methodology to isolate four mutations that cause kidney cysts; we identified novel alleles in two ciliary genes as well as two novel mutants. The WES approach described here does not require specialized infrastructure or training and is therefore widely accessible. This methodology should thus help facilitate genetic screens and expedite the identification of mutants that can inform basic biological processes and the causality of genetic disorders in humans.

Authors
Ryan, S; Willer, J; Marjoram, L; Bagwell, J; Mankiewicz, J; Leshchiner, I; Goessling, W; Bagnat, M; Katsanis, N
MLA Citation
Ryan, S, Willer, J, Marjoram, L, Bagwell, J, Mankiewicz, J, Leshchiner, I, Goessling, W, Bagnat, M, and Katsanis, N. "Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish." Development 140.21 (November 2013): 4445-4451.
PMID
24130329
Source
pubmed
Published In
Development (Cambridge)
Volume
140
Issue
21
Publish Date
2013
Start Page
4445
End Page
4451
DOI
10.1242/dev.101170

The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex.

CCDC28B encodes a coiled coil domain-containing protein involved in ciliogenesis that was originally identified as a second site modifier of the ciliopathy Bardet-Biedl syndrome. We have previously shown that the depletion of CCDC28B leads to shortened cilia; however, the mechanism underlying how this protein controls ciliary length is unknown. Here, we show that CCDC28B interacts with SIN1, a component of the mTOR complex 2 (mTORC2), and that this interaction is important both in the context of mTOR signaling and in a hitherto unknown, mTORC-independent role of SIN1 in cilia biology. We show that CCDC28B is a positive regulator of mTORC2, participating in its assembly/stability and modulating its activity, while not affecting mTORC1 function. Further, we show that Ccdc28b regulates cilia length in vivo, at least in part, through its interaction with Sin1. Importantly, depletion of Rictor, another core component of mTORC2, does not result in shortened cilia. Taken together, our findings implicate CCDC28B in the regulation of mTORC2, and uncover a novel function of SIN1 regulating cilia length that is likely independent of mTOR signaling.

Authors
Cardenas-Rodriguez, M; Irigoín, F; Osborn, DPS; Gascue, C; Katsanis, N; Beales, PL; Badano, JL
MLA Citation
Cardenas-Rodriguez, M, Irigoín, F, Osborn, DPS, Gascue, C, Katsanis, N, Beales, PL, and Badano, JL. "The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex." Hum Mol Genet 22.20 (October 15, 2013): 4031-4042.
PMID
23727834
Source
pubmed
Published In
Human Molecular Genetics
Volume
22
Issue
20
Publish Date
2013
Start Page
4031
End Page
4042
DOI
10.1093/hmg/ddt253

Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4.

Fuchs corneal dystrophy (FCD) is a hereditary dystrophy of the corneal endothelium and is responsible for majority of the corneal transplantation performed in the United States. Here, we describe three generations of a family with 12 individuals affected by late-onset FCD and in which three individuals are unaffected. Genome-wide mapping provided suggestive linkage at two loci on chromosomal arms 3p and 15q. Alleles at either locus alone were not sufficient to explain FCD; however, considered together, both loci could explain the disorder in this pedigree. Subsequent next-generation sequencing identified a nonsense mutation in AGBL1 in the 15q locus; this mutation would result in a premature termination of AGBL1. Consistent with a causal role for this transcript, further sequencing of our cohort of late-onset-FCD-affected individuals identified two cases harboring the same nonsense mutation and a further three unrelated individuals bearing a second missense allele. AGBL1 encodes a glutamate decarboxylase previously identified in serial analysis of gene expression of corneal endothelium, a finding confirmed by immunohistochemical staining. Wild-type AGBL1 localizes predominantly to the cytoplasm; in sharp contrast, the truncated protein showed distinct nuclear localization. Finally, we show that AGBL1 interacts biochemically with the FCD-associated protein TCF4 and that the mutations found in our cohort of FCD individuals diminish this interaction. Taken together, our data identify a locus for FCD, extend the complex genetic architecture of the disorder, provide direct evidence for the involvement of TCF4 in FCD pathogenesis, and begin to explain how causal FCD mutations affect discrete biochemical complexes.

Authors
Riazuddin, SA; Vasanth, S; Katsanis, N; Gottsch, JD
MLA Citation
Riazuddin, SA, Vasanth, S, Katsanis, N, and Gottsch, JD. "Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4." Am J Hum Genet 93.4 (October 3, 2013): 758-764.
PMID
24094747
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
93
Issue
4
Publish Date
2013
Start Page
758
End Page
764
DOI
10.1016/j.ajhg.2013.08.010

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene.

We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ~446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonine-protein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome.

Authors
Nishiguchi, KM; Tearle, RG; Liu, YP; Oh, EC; Miyake, N; Benaglio, P; Harper, S; Koskiniemi-Kuendig, H; Venturini, G; Sharon, D; Koenekoop, RK; Nakamura, M; Kondo, M; Ueno, S; Yasuma, TR; Beckmann, JS; Ikegawa, S; Matsumoto, N; Terasaki, H; Berson, EL; Katsanis, N; Rivolta, C
MLA Citation
Nishiguchi, KM, Tearle, RG, Liu, YP, Oh, EC, Miyake, N, Benaglio, P, Harper, S, Koskiniemi-Kuendig, H, Venturini, G, Sharon, D, Koenekoop, RK, Nakamura, M, Kondo, M, Ueno, S, Yasuma, TR, Beckmann, JS, Ikegawa, S, Matsumoto, N, Terasaki, H, Berson, EL, Katsanis, N, and Rivolta, C. "Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene." Proc Natl Acad Sci U S A 110.40 (October 1, 2013): 16139-16144.
PMID
24043777
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
40
Publish Date
2013
Start Page
16139
End Page
16144
DOI
10.1073/pnas.1308243110

In vivo modeling of the morbid human genome using Danio rerio.

Here, we present methods for the development of assays to query potentially clinically significant nonsynonymous changes using in vivo complementation in zebrafish. Zebrafish (Danio rerio) are a useful animal system due to their experimental tractability; embryos are transparent to enable facile viewing, undergo rapid development ex vivo, and can be genetically manipulated. These aspects have allowed for significant advances in the analysis of embryogenesis, molecular processes, and morphogenetic signaling. Taken together, the advantages of this vertebrate model make zebrafish highly amenable to modeling the developmental defects in pediatric disease, and in some cases, adult-onset disorders. Because the zebrafish genome is highly conserved with that of humans (~70% orthologous), it is possible to recapitulate human disease states in zebrafish. This is accomplished either through the injection of mutant human mRNA to induce dominant negative or gain of function alleles, or utilization of morpholino (MO) antisense oligonucleotides to suppress genes to mimic loss of function variants. Through complementation of MO-induced phenotypes with capped human mRNA, our approach enables the interpretation of the deleterious effect of mutations on human protein sequence based on the ability of mutant mRNA to rescue a measurable, physiologically relevant phenotype. Modeling of the human disease alleles occurs through microinjection of zebrafish embryos with MO and/or human mRNA at the 1-4 cell stage, and phenotyping up to seven days post fertilization (dpf). This general strategy can be extended to a wide range of disease phenotypes, as demonstrated in the following protocol. We present our established models for morphogenetic signaling, craniofacial, cardiac, vascular integrity, renal function, and skeletal muscle disorder phenotypes, as well as others.

Authors
Niederriter, AR; Davis, EE; Golzio, C; Oh, EC; Tsai, I-C; Katsanis, N
MLA Citation
Niederriter, AR, Davis, EE, Golzio, C, Oh, EC, Tsai, I-C, and Katsanis, N. "In vivo modeling of the morbid human genome using Danio rerio. (Published online)" J Vis Exp 78 (August 24, 2013): e50338-.
PMID
23995499
Source
pubmed
Published In
Journal of Visualized Experiments
Issue
78
Publish Date
2013
Start Page
e50338
DOI
10.3791/50338

TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

Authors
Wiszniewski, W; Hunter, JV; Hanchard, NA; Willer, JR; Shaw, C; Tian, Q; Illner, A; Wang, X; Cheung, SW; Patel, A; Campbell, IM; Gelowani, V; Hixson, P; Ester, AR; Azamian, MS; Potocki, L; Zapata, G; Hernandez, PP; Ramocki, MB; Santos-Cortez, RLP; Wang, G; York, MK; Justice, MJ; Chu, ZD; Bader, PI; Omo-Griffith, L; Madduri, NS; Scharer, G; Crawford, HP; Yanatatsaneejit, P; Eifert, A; Kerr, J; Bacino, CA; Franklin, AIA; Goin-Kochel, RP; Simpson, G; Immken, L; Haque, ME; Stosic, M; Williams, MD et al.
MLA Citation
Wiszniewski, W, Hunter, JV, Hanchard, NA, Willer, JR, Shaw, C, Tian, Q, Illner, A, Wang, X, Cheung, SW, Patel, A, Campbell, IM, Gelowani, V, Hixson, P, Ester, AR, Azamian, MS, Potocki, L, Zapata, G, Hernandez, PP, Ramocki, MB, Santos-Cortez, RLP, Wang, G, York, MK, Justice, MJ, Chu, ZD, Bader, PI, Omo-Griffith, L, Madduri, NS, Scharer, G, Crawford, HP, Yanatatsaneejit, P, Eifert, A, Kerr, J, Bacino, CA, Franklin, AIA, Goin-Kochel, RP, Simpson, G, Immken, L, Haque, ME, Stosic, M, and Williams, MD et al. "TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities." Am J Hum Genet 93.2 (August 8, 2013): 197-210.
PMID
23810381
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
93
Issue
2
Publish Date
2013
Start Page
197
End Page
210
DOI
10.1016/j.ajhg.2013.05.027

ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.

The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.

Authors
Hjeij, R; Lindstrand, A; Francis, R; Zariwala, MA; Liu, X; Li, Y; Damerla, R; Dougherty, GW; Abouhamed, M; Olbrich, H; Loges, NT; Pennekamp, P; Davis, EE; Carvalho, CMB; Pehlivan, D; Werner, C; Raidt, J; Köhler, G; Häffner, K; Reyes-Mugica, M; Lupski, JR; Leigh, MW; Rosenfeld, M; Morgan, LC; Knowles, MR; Lo, CW; Katsanis, N; Omran, H
MLA Citation
Hjeij, R, Lindstrand, A, Francis, R, Zariwala, MA, Liu, X, Li, Y, Damerla, R, Dougherty, GW, Abouhamed, M, Olbrich, H, Loges, NT, Pennekamp, P, Davis, EE, Carvalho, CMB, Pehlivan, D, Werner, C, Raidt, J, Köhler, G, Häffner, K, Reyes-Mugica, M, Lupski, JR, Leigh, MW, Rosenfeld, M, Morgan, LC, Knowles, MR, Lo, CW, Katsanis, N, and Omran, H. "ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry." Am J Hum Genet 93.2 (August 8, 2013): 357-367.
PMID
23849778
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
93
Issue
2
Publish Date
2013
Start Page
357
End Page
367
DOI
10.1016/j.ajhg.2013.06.009

A functional variant in the CFI gene confers a high risk of age-related macular degeneration.

Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 × 10⁻⁶; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.

Authors
van de Ven, JPH; Nilsson, SC; Tan, PL; Buitendijk, GHS; Ristau, T; Mohlin, FC; Nabuurs, SB; Schoenmaker-Koller, FE; Smailhodzic, D; Campochiaro, PA; Zack, DJ; Duvvari, MR; Bakker, B; Paun, CC; Boon, CJF; Uitterlinden, AG; Liakopoulos, S; Klevering, BJ; Fauser, S; Daha, MR; Katsanis, N; Klaver, CCW; Blom, AM; Hoyng, CB; den Hollander, AI
MLA Citation
van de Ven, JPH, Nilsson, SC, Tan, PL, Buitendijk, GHS, Ristau, T, Mohlin, FC, Nabuurs, SB, Schoenmaker-Koller, FE, Smailhodzic, D, Campochiaro, PA, Zack, DJ, Duvvari, MR, Bakker, B, Paun, CC, Boon, CJF, Uitterlinden, AG, Liakopoulos, S, Klevering, BJ, Fauser, S, Daha, MR, Katsanis, N, Klaver, CCW, Blom, AM, Hoyng, CB, and den Hollander, AI. "A functional variant in the CFI gene confers a high risk of age-related macular degeneration." Nat Genet 45.7 (July 2013): 813-817.
PMID
23685748
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
7
Publish Date
2013
Start Page
813
End Page
817
DOI
10.1038/ng.2640

Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare pediatric ciliopathy characterized by marked clinical variability and extensive genetic heterogeneity. Typical diagnosis of BBS is secured at a median of 9 years of age, and sometimes well into adolescence. Here, we report a patient in whom prenatal detection of increased nuchal fold, enlarged echogenic kidneys, and polydactyly prompted us to screen the most commonly mutated genes in BBS and the phenotypically and genetically overlapping ciliopathy, Meckel-Gruber syndrome (MKS). We identified the common Met390Arg mutation in BBS1 in compound heterozygosity with a novel intronic variant of unknown significance (VUS). Testing of mRNA harvested from primary foreskin fibroblasts obtained shortly after birth revealed the VUS to induce a cryptic splice site, which in turn led to a premature termination and mRNA degradation. To our knowledge, this is the earliest diagnosis of BBS in the absence of other affected individuals in the family, and exemplifies how combining clinical assessment with genetic and timely assays of variant pathogenicity can inform clinical diagnosis and assist with patient management in the prenatal and neonatal setting.

Authors
Ashkinadze, E; Rosen, T; Brooks, SS; Katsanis, N; Davis, EE
MLA Citation
Ashkinadze, E, Rosen, T, Brooks, SS, Katsanis, N, and Davis, EE. "Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome." Clin Genet 83.6 (June 2013): 553-559.
PMID
22998390
Source
pubmed
Published In
Clinical Genetics
Volume
83
Issue
6
Publish Date
2013
Start Page
553
End Page
559
DOI
10.1111/cge.12022

Molecular genetic testing and the future of clinical genomics.

Genomic technologies are reaching the point of being able to detect genetic variation in patients at high accuracy and reduced cost, offering the promise of fundamentally altering medicine. Still, although scientists and policy advisers grapple with how to interpret and how to handle the onslaught and ambiguity of genome-wide data, established and well-validated molecular technologies continue to have an important role, especially in regions of the world that have more limited access to next-generation sequencing capabilities. Here we review the range of methods currently available in a clinical setting as well as emerging approaches in clinical molecular diagnostics. In parallel, we outline implementation challenges that will be necessary to address to ensure the future of genetic medicine.

Authors
Katsanis, SH; Katsanis, N
MLA Citation
Katsanis, SH, and Katsanis, N. "Molecular genetic testing and the future of clinical genomics." Nature reviews. Genetics 14.6 (June 2013): 415-426. (Review)
PMID
23681062
Source
epmc
Published In
Nature Reviews Genetics
Volume
14
Issue
6
Publish Date
2013
Start Page
415
End Page
426
DOI
10.1038/nrg3493

Genetic architecture of reciprocal CNVs.

Copy number variants (CNVs) represent a frequent type of lesion in human genetic disorders that typically affects numerous genes simultaneously. This has raised the challenge of understanding which genes within a CNV drive clinical phenotypes. Although CNVs can arise by multiple mechanisms, a subset is driven by local genomic architecture permissive to recombination events that can lead to both deletions and duplications. Phenotypic analyses of patients with such reciprocal CNVs have revealed instances in which the phenotype is either identical or mirrored; strikingly, molecular studies have shown that such phenotypes are often driven by reciprocal dosage defects of the same transcript. Here we explore how these observations can help the dissection of CNVs and inform the genetic architecture of CNV-induced disorders.

Authors
Golzio, C; Katsanis, N
MLA Citation
Golzio, C, and Katsanis, N. "Genetic architecture of reciprocal CNVs." Curr Opin Genet Dev 23.3 (June 2013): 240-248. (Review)
PMID
23747035
Source
pubmed
Published In
Current Opinion in Genetics and Development
Volume
23
Issue
3
Publish Date
2013
Start Page
240
End Page
248
DOI
10.1016/j.gde.2013.04.013

Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.

BACKGROUND: The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS: We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS: Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS: The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).

Authors
Margolin, DH; Kousi, M; Chan, Y-M; Lim, ET; Schmahmann, JD; Hadjivassiliou, M; Hall, JE; Adam, I; Dwyer, A; Plummer, L; Aldrin, SV; O'Rourke, J; Kirby, A; Lage, K; Milunsky, A; Milunsky, JM; Chan, J; Hedley-Whyte, ET; Daly, MJ; Katsanis, N; Seminara, SB
MLA Citation
Margolin, DH, Kousi, M, Chan, Y-M, Lim, ET, Schmahmann, JD, Hadjivassiliou, M, Hall, JE, Adam, I, Dwyer, A, Plummer, L, Aldrin, SV, O'Rourke, J, Kirby, A, Lage, K, Milunsky, A, Milunsky, JM, Chan, J, Hedley-Whyte, ET, Daly, MJ, Katsanis, N, and Seminara, SB. "Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination." N Engl J Med 368.21 (May 23, 2013): 1992-2003.
PMID
23656588
Source
pubmed
Published In
The New England journal of medicine
Volume
368
Issue
21
Publish Date
2013
Start Page
1992
End Page
2003
DOI
10.1056/NEJMoa1215993

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Authors
Fritsche, LG; Chen, W; Schu, M; Yaspan, BL; Yu, Y; Thorleifsson, G; Zack, DJ; Arakawa, S; Cipriani, V; Ripke, S; Igo, RP; Buitendijk, GHS; Sim, X; Weeks, DE; Guymer, RH; Merriam, JE; Francis, PJ; Hannum, G; Agarwal, A; Armbrecht, AM; Audo, I; Aung, T; Barile, GR; Benchaboune, M; Bird, AC; Bishop, PN; Branham, KE; Brooks, M; Brucker, AJ; Cade, WH; Cain, MS; Campochiaro, PA; Chan, C-C; Cheng, C-Y; Chew, EY; Chin, KA; Chowers, I; Clayton, DG; Cojocaru, R; Conley, YP; Cornes, BK; Daly, MJ et al.
MLA Citation
Fritsche, LG, Chen, W, Schu, M, Yaspan, BL, Yu, Y, Thorleifsson, G, Zack, DJ, Arakawa, S, Cipriani, V, Ripke, S, Igo, RP, Buitendijk, GHS, Sim, X, Weeks, DE, Guymer, RH, Merriam, JE, Francis, PJ, Hannum, G, Agarwal, A, Armbrecht, AM, Audo, I, Aung, T, Barile, GR, Benchaboune, M, Bird, AC, Bishop, PN, Branham, KE, Brooks, M, Brucker, AJ, Cade, WH, Cain, MS, Campochiaro, PA, Chan, C-C, Cheng, C-Y, Chew, EY, Chin, KA, Chowers, I, Clayton, DG, Cojocaru, R, Conley, YP, Cornes, BK, and Daly, MJ et al. "Seven new loci associated with age-related macular degeneration." Nat Genet 45.4 (April 2013): 433-439e2.
PMID
23455636
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
4
Publish Date
2013
Start Page
433
End Page
439e2
DOI
10.1038/ng.2578

Mutations in LRRC50 predispose zebrafish and humans to seminomas.

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.

Authors
Basten, SG; Davis, EE; Gillis, AJM; van Rooijen, E; Stoop, H; Babala, N; Logister, I; Heath, ZG; Jonges, TN; Katsanis, N; Voest, EE; van Eeden, FJ; Medema, RH; Ketting, RF; Schulte-Merker, S; Looijenga, LHJ; Giles, RH
MLA Citation
Basten, SG, Davis, EE, Gillis, AJM, van Rooijen, E, Stoop, H, Babala, N, Logister, I, Heath, ZG, Jonges, TN, Katsanis, N, Voest, EE, van Eeden, FJ, Medema, RH, Ketting, RF, Schulte-Merker, S, Looijenga, LHJ, and Giles, RH. "Mutations in LRRC50 predispose zebrafish and humans to seminomas." PLoS Genet 9.4 (April 2013): e1003384-.
PMID
23599692
Source
pubmed
Published In
PLoS genetics
Volume
9
Issue
4
Publish Date
2013
Start Page
e1003384
DOI
10.1371/journal.pgen.1003384

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

Authors
Beunders, G; Voorhoeve, E; Golzio, C; Pardo, LM; Rosenfeld, JA; Talkowski, ME; Simonic, I; Lionel, AC; Vergult, S; Pyatt, RE; van de Kamp, J; Nieuwint, A; Weiss, MM; Rizzu, P; Verwer, LENI; van Spaendonk, RML; Shen, Y; Wu, B-L; Yu, T; Yu, Y; Chiang, C; Gusella, JF; Lindgren, AM; Morton, CC; van Binsbergen, E; Bulk, S; van Rossem, E; Vanakker, O; Armstrong, R; Park, S-M; Greenhalgh, L; Maye, U; Neill, NJ; Abbott, KM; Sell, S; Ladda, R; Farber, DM; Bader, PI; Cushing, T; Drautz, JM; Konczal, L et al.
MLA Citation
Beunders, G, Voorhoeve, E, Golzio, C, Pardo, LM, Rosenfeld, JA, Talkowski, ME, Simonic, I, Lionel, AC, Vergult, S, Pyatt, RE, van de Kamp, J, Nieuwint, A, Weiss, MM, Rizzu, P, Verwer, LENI, van Spaendonk, RML, Shen, Y, Wu, B-L, Yu, T, Yu, Y, Chiang, C, Gusella, JF, Lindgren, AM, Morton, CC, van Binsbergen, E, Bulk, S, van Rossem, E, Vanakker, O, Armstrong, R, Park, S-M, Greenhalgh, L, Maye, U, Neill, NJ, Abbott, KM, Sell, S, Ladda, R, Farber, DM, Bader, PI, Cushing, T, Drautz, JM, and Konczal, L et al. "Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus." Am J Hum Genet 92.2 (February 7, 2013): 210-220.
PMID
23332918
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
92
Issue
2
Publish Date
2013
Start Page
210
End Page
220
DOI
10.1016/j.ajhg.2012.12.011

Context-dependent regulation of Wnt signaling through the primary cilium.

The primary cilium is a highly conserved environmental sensor and modulator of fluid movement in tubular structures. The growing recognition of mutations among its many components has led to the discovery of new disorders collectively called ciliopathies. Ciliary dysfunction disturbs a variety of signaling pathways along its basal body and axoneme that are critical for embryonic development and cell and organ homeostasis. Among the many pathways, here we discuss the emerging role of Wnt proteins in morphogenic signaling and ciliary biology during health and disease.

Authors
Oh, EC; Katsanis, N
MLA Citation
Oh, EC, and Katsanis, N. "Context-dependent regulation of Wnt signaling through the primary cilium." J Am Soc Nephrol 24.1 (January 2013): 10-18. (Review)
PMID
23123400
Source
pubmed
Published In
Journal of the American Society of Nephrology : JASN
Volume
24
Issue
1
Publish Date
2013
Start Page
10
End Page
18
DOI
10.1681/ASN.2012050526

Next-generation sequencing of the human olfactory receptors.

Humans have approximately 400 intact olfactory receptors (ORs). Among this set there are a large number of variations between individuals, a subset of which affects receptor function and can lead to interindividual variation in olfactory perception. Technological progress and cost erosion in next-generation sequencing have given us the opportunity to determine the sequence of the entire OR gene set with high fidelity and to measure the extent of variation in this functional module across many individuals. Given that whole genome sequencing remains prohibitively expensive for this purpose, especially since the OR sub-genome represents only ~0.0125 % of the human genome, we have designed a targeted capture method to enrich the OR for next-generation sequencing, which we describe here. Using this method we have been able to sequence an individual's OR sub-genome with high coverage, enabling us to identify variation with high sensitivity and specificity. This method can be used to accurate assess the amount of variability in this module and to identify the functional role of individual ORs in olfactory perception.

Authors
Mainland, JD; Willer, JR; Matsunami, H; Katsanis, N
MLA Citation
Mainland, JD, Willer, JR, Matsunami, H, and Katsanis, N. "Next-generation sequencing of the human olfactory receptors." Methods Mol Biol 1003 (2013): 133-147.
PMID
23585039
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
1003
Publish Date
2013
Start Page
133
End Page
147
DOI
10.1007/978-1-62703-377-0_10

Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes.

PURPOSE: Stickler syndrome is an arthro-ophthalmopathy with phenotypic overlap with Wagner syndrome. The common Stickler syndrome type I is inherited as an autosomal dominant trait, with causal mutations in collagen type II alpha 1 (COL2A1). Wagner syndrome is associated with mutations in versican (VCAN), which encodes for a chondroitin sulfate proteoglycan. A three-generation Caucasian family variably diagnosed with either syndrome was screened for sequence variants in the COL2A1 and VCAN genes. METHODS: Genomic DNA samples derived from saliva were collected from all family members (six affected and four unaffected individuals). Complete sequencing of COL2A1 and VCAN was performed on two affected individuals. Direct sequencing of remaining family members was conducted if the discovered variants followed segregation. RESULTS: A base-pair substitution (c.258C>A) in exon 2 of COL2A1 cosegregated with familial disease status. This known mutation occurs in a highly conserved site that causes a premature stop codon (p.C86X). The mutation was not seen in 1,142 ethnically matched control DNA samples. CONCLUSIONS: Premature stop codons in COL2A1 exon 2 lead to a Stickler syndrome type I ocular-only phenotype with few or no systemic manifestations. Mutation screening of COL2A1 exon 2 in families with autosomal dominant vitreoretinopathy is important for accurate clinical diagnosis.

Authors
Tran-Viet, K-N; Soler, V; Quiette, V; Powell, C; Yanovitch, T; Metlapally, R; Luo, X; Katsanis, N; Nading, E; Young, TL
MLA Citation
Tran-Viet, K-N, Soler, V, Quiette, V, Powell, C, Yanovitch, T, Metlapally, R, Luo, X, Katsanis, N, Nading, E, and Young, TL. "Mutation in collagen II alpha 1 isoforms delineates Stickler and Wagner syndrome phenotypes. (Published online)" Mol Vis 19 (2013): 759-766.
PMID
23592912
Source
pubmed
Published In
Molecular vision
Volume
19
Publish Date
2013
Start Page
759
End Page
766

Renal cystic disease: from mechanisms to drug development

Cystic kidney disease, one of the leading causes of end stage renal disease (ESRD), encompasses a group of genetic disorders defined by the presence and the expansion of cysts at various positions in the nephron. Recent studies in humans and model organisms have identified a direct relationship between cyst formation and dysfunctional ciliary proteins, and have suggested that ciliary dysfunction is a major driver of cystogenesis. However, the fact that the primary cilium is now understood to be a central coordinator for multiple cellular signaling pathways has complicated our mechanistic understanding of cystogenesis and has offered diverse and sometimes contradictory paths to therapeutic designs. Here, we will focus on the recent findings which underlie the molecular mechanisms of cyst formation in the kidney and we discuss how insights of these studies are beginning to offer routes toward the development of treatment paradigms and the promise of preclinical and clinical trials. © 2013.

Authors
Tsai, IC; Katsanis, N
MLA Citation
Tsai, IC, and Katsanis, N. "Renal cystic disease: from mechanisms to drug development." Drug Discovery Today: Disease Mechanisms (2013).
Source
scival
Published In
Drug Discovery Today: Disease Mechanisms
Publish Date
2013
DOI
10.1016/j.ddmec.2013.03.003

Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare pediatric ciliopathy characterized by marked clinical variability and extensive genetic heterogeneity. Typical diagnosis of BBS is secured at a median of 9 years of age, and sometimes well into adolescence. Here, we report a patient in whom prenatal detection of increased nuchal fold, enlarged echogenic kidneys, and polydactyly prompted us to screen the most commonly mutated genes in BBS and the phenotypically and genetically overlapping ciliopathy, Meckel-Gruber syndrome (MKS). We identified the common Met390Arg mutation in BBS1 in compound heterozygosity with a novel intronic variant of unknown significance (VUS). Testing of mRNA harvested from primary foreskin fibroblasts obtained shortly after birth revealed the VUS to induce a cryptic splice site, which in turn led to a premature termination and mRNA degradation. To our knowledge, this is the earliest diagnosis of BBS in the absence of other affected individuals in the family, and exemplifies how combining clinical assessment with genetic and timely assays of variant pathogenicity can inform clinical diagnosis and assist with patient management in the prenatal and neonatal setting. © 2012 John Wiley & Sons A/S.

Authors
Ashkinadze, E; Rosen, T; Brooks, S; Katsanis, N; Davis, EE
MLA Citation
Ashkinadze, E, Rosen, T, Brooks, S, Katsanis, N, and Davis, EE. "Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome." Clinical Genetics 83.6 (2013): 553-559.
Source
scival
Published In
Clinical Genetics
Volume
83
Issue
6
Publish Date
2013
Start Page
553
End Page
559
DOI
10.1111/cge.12022

A functional variant in the CFI gene confers a high risk of age-related macular degeneration

Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 × 10 -6; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD. © 2013 Nature America, Inc. All rights reserved.

Authors
Ven, JPHVD; Nilsson, SC; Tan, PL; Buitendijk, GHS; Ristau, T; Mohlin, FC; Nabuurs, SB; Schoenmaker-Koller, FE; Smailhodzic, D; Campochiaro, PA; Zack, DJ; Duvvari, MR; Bakker, B; Paun, CC; Boon, CJF; Uitterlinden, AG; Liakopoulos, S; Klevering, BJ; Fauser, S; Daha, MR; Katsanis, N; Klaver, CCW; Blom, AM; Hoyng, CB; Hollander, AID
MLA Citation
Ven, JPHVD, Nilsson, SC, Tan, PL, Buitendijk, GHS, Ristau, T, Mohlin, FC, Nabuurs, SB, Schoenmaker-Koller, FE, Smailhodzic, D, Campochiaro, PA, Zack, DJ, Duvvari, MR, Bakker, B, Paun, CC, Boon, CJF, Uitterlinden, AG, Liakopoulos, S, Klevering, BJ, Fauser, S, Daha, MR, Katsanis, N, Klaver, CCW, Blom, AM, Hoyng, CB, and Hollander, AID. "A functional variant in the CFI gene confers a high risk of age-related macular degeneration." Nature Genetics 45.7 (2013): 813-817.
Source
scival
Published In
Nature Genetics
Volume
45
Issue
7
Publish Date
2013
Start Page
813
End Page
817
DOI
10.1038/ng.2640

Genetic architecture of reciprocal CNVs

Copy number variants (CNVs) represent a frequent type of lesion in human genetic disorders that typically affects numerous genes simultaneously. This has raised the challenge of understanding which genes within a CNV drive clinical phenotypes. Although CNVs can arise by multiple mechanisms, a subset is driven by local genomic architecture permissive to recombination events that can lead to both deletions and duplications. Phenotypic analyses of patients with such reciprocal CNVs have revealed instances in which the phenotype is either identical or mirrored; strikingly, molecular studies have shown that such phenotypes are often driven by reciprocal dosage defects of the same transcript. Here we explore how these observations can help the dissection of CNVs and inform the genetic architecture of CNV-induced disorders. © 2013 Elsevier Ltd.

Authors
Golzio, C; Katsanis, N
MLA Citation
Golzio, C, and Katsanis, N. "Genetic architecture of reciprocal CNVs." Current Opinion in Genetics and Development 23.3 (2013): 240-248.
Source
scival
Published In
Current Opinion in Genetics & Development
Volume
23
Issue
3
Publish Date
2013
Start Page
240
End Page
248
DOI
10.1016/j.gde.2013.04.013

Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.

We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.

Authors
Schuurs-Hoeijmakers, JHM; Oh, EC; Vissers, LELM; Swinkels, MEM; Gilissen, C; Willemsen, MA; Holvoet, M; Steehouwer, M; Veltman, JA; de Vries, BBA; van Bokhoven, H; de Brouwer, APM; Katsanis, N; Devriendt, K; Brunner, HG
MLA Citation
Schuurs-Hoeijmakers, JHM, Oh, EC, Vissers, LELM, Swinkels, MEM, Gilissen, C, Willemsen, MA, Holvoet, M, Steehouwer, M, Veltman, JA, de Vries, BBA, van Bokhoven, H, de Brouwer, APM, Katsanis, N, Devriendt, K, and Brunner, HG. "Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome." Am J Hum Genet 91.6 (December 7, 2012): 1122-1127.
PMID
23159249
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
91
Issue
6
Publish Date
2012
Start Page
1122
End Page
1127
DOI
10.1016/j.ajhg.2012.10.013

Endoglin mediates fibronectin/α5β1 integrin and TGF-β pathway crosstalk in endothelial cells.

Both the transforming growth factor β (TGF-β) and integrin signalling pathways have well-established roles in angiogenesis. However, how these pathways integrate to regulate angiogenesis is unknown. Here, we show that the extracellular matrix component, fibronectin, and its cellular receptor, α5β1 integrin, specifically increase TGF-β1- and BMP-9-induced Smad1/5/8 phosphorylation via the TGF-β superfamily receptors endoglin and activin-like kinase-1 (ALK1). Fibronectin and α5β1 integrin increase Smad1/5/8 signalling by promoting endoglin/ALK1 cell surface complex formation. In a reciprocal manner, TGF-β1 activates α5β1 integrin and downstream signalling to focal adhesion kinase (FAK) in an endoglin-dependent manner. α5β1 integrin and endoglin form a complex on the cell surface and co-internalize, with their internalization regulating α5β1 integrin activation and signalling. Functionally, endoglin-mediated fibronectin/α5β1 integrin and TGF-β pathway crosstalk alter the responses of endothelial cells to TGF-β1, switching TGF-β1 from a promoter to a suppressor of migration, inhibiting TGF-β1-mediated apoptosis to promote capillary stability, and partially mediating developmental angiogenesis in vivo. These studies provide a novel mechanism for the regulation of TGF-β superfamily signalling and endothelial function through crosstalk with integrin signalling pathways.

Authors
Tian, H; Mythreye, K; Golzio, C; Katsanis, N; Blobe, GC
MLA Citation
Tian, H, Mythreye, K, Golzio, C, Katsanis, N, and Blobe, GC. "Endoglin mediates fibronectin/α5β1 integrin and TGF-β pathway crosstalk in endothelial cells." EMBO J 31.19 (October 3, 2012): 3885-3900.
PMID
22940691
Source
pubmed
Published In
EMBO Journal
Volume
31
Issue
19
Publish Date
2012
Start Page
3885
End Page
3900
DOI
10.1038/emboj.2012.246

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

Authors
Sobrin, L; Ripke, S; Yu, Y; Fagerness, J; Bhangale, TR; Tan, PL; Souied, EH; Buitendijk, GHS; Merriam, JE; Richardson, AJ; Raychaudhuri, S; Reynolds, R; Chin, KA; Lee, AY; Leveziel, N; Zack, DJ; Campochiaro, P; Smith, RT; Barile, GR; Hogg, RE; Chakravarthy, U; Behrens, TW; Uitterlinden, AG; van Duijn, CM; Vingerling, JR; Brantley, MA; Baird, PN; Klaver, CCW; Allikmets, R; Katsanis, N; Graham, RR; Ioannidis, JPA; Daly, MJ; Seddon, JM
MLA Citation
Sobrin, L, Ripke, S, Yu, Y, Fagerness, J, Bhangale, TR, Tan, PL, Souied, EH, Buitendijk, GHS, Merriam, JE, Richardson, AJ, Raychaudhuri, S, Reynolds, R, Chin, KA, Lee, AY, Leveziel, N, Zack, DJ, Campochiaro, P, Smith, RT, Barile, GR, Hogg, RE, Chakravarthy, U, Behrens, TW, Uitterlinden, AG, van Duijn, CM, Vingerling, JR, Brantley, MA, Baird, PN, Klaver, CCW, Allikmets, R, Katsanis, N, Graham, RR, Ioannidis, JPA, Daly, MJ, and Seddon, JM. "Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes." Ophthalmology 119.9 (September 2012): 1874-1885.
PMID
22705344
Source
pubmed
Published In
Ophthalmology: Journal of The American Academy of Ophthalmology
Volume
119
Issue
9
Publish Date
2012
Start Page
1874
End Page
1885
DOI
10.1016/j.ophtha.2012.03.014

Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model.

Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88Tg737Rpw mice, also known as ORPK mice)5 have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells.

Authors
McIntyre, JC; Davis, EE; Joiner, A; Williams, CL; Tsai, I-C; Jenkins, PM; McEwen, DP; Zhang, L; Escobado, J; Thomas, S; Szymanska, K; Johnson, CA; Beales, PL; Green, ED; Mullikin, JC; NISC Comparative Sequencing Program, ; Sabo, A; Muzny, DM; Gibbs, RA; Attié-Bitach, T; Yoder, BK; Reed, RR; Katsanis, N; Martens, JR
MLA Citation
McIntyre, JC, Davis, EE, Joiner, A, Williams, CL, Tsai, I-C, Jenkins, PM, McEwen, DP, Zhang, L, Escobado, J, Thomas, S, Szymanska, K, Johnson, CA, Beales, PL, Green, ED, Mullikin, JC, NISC Comparative Sequencing Program, , Sabo, A, Muzny, DM, Gibbs, RA, Attié-Bitach, T, Yoder, BK, Reed, RR, Katsanis, N, and Martens, JR. "Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model." Nat Med 18.9 (September 2012): 1423-1428.
PMID
22941275
Source
pubmed
Published In
Nature Medicine
Volume
18
Issue
9
Publish Date
2012
Start Page
1423
End Page
1428
DOI
10.1038/nm.2860

Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.

Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

Authors
Chaki, M; Airik, R; Ghosh, AK; Giles, RH; Chen, R; Slaats, GG; Wang, H; Hurd, TW; Zhou, W; Cluckey, A; Gee, HY; Ramaswami, G; Hong, C-J; Hamilton, BA; Cervenka, I; Ganji, RS; Bryja, V; Arts, HH; van Reeuwijk, J; Oud, MM; Letteboer, SJF; Roepman, R; Husson, H; Ibraghimov-Beskrovnaya, O; Yasunaga, T; Walz, G; Eley, L; Sayer, JA; Schermer, B; Liebau, MC; Benzing, T; Le Corre, S; Drummond, I; Janssen, S; Allen, SJ; Natarajan, S; O'Toole, JF; Attanasio, M; Saunier, S; Antignac, C; Koenekoop, RK et al.
MLA Citation
Chaki, M, Airik, R, Ghosh, AK, Giles, RH, Chen, R, Slaats, GG, Wang, H, Hurd, TW, Zhou, W, Cluckey, A, Gee, HY, Ramaswami, G, Hong, C-J, Hamilton, BA, Cervenka, I, Ganji, RS, Bryja, V, Arts, HH, van Reeuwijk, J, Oud, MM, Letteboer, SJF, Roepman, R, Husson, H, Ibraghimov-Beskrovnaya, O, Yasunaga, T, Walz, G, Eley, L, Sayer, JA, Schermer, B, Liebau, MC, Benzing, T, Le Corre, S, Drummond, I, Janssen, S, Allen, SJ, Natarajan, S, O'Toole, JF, Attanasio, M, Saunier, S, Antignac, C, and Koenekoop, RK et al. "Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling." Cell 150.3 (August 3, 2012): 533-548.
PMID
22863007
Source
pubmed
Published In
Cell
Volume
150
Issue
3
Publish Date
2012
Start Page
533
End Page
548
DOI
10.1016/j.cell.2012.06.028

Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis.

Endoglin (CD105) is an endothelial-specific transforming growth factor β (TGF-β) coreceptor essential for angiogenesis and vascular homeostasis. Although endoglin dysfunction contributes to numerous vascular conditions, the mechanism of endoglin action remains poorly understood. Here we report a novel mechanism in which endoglin and Gα-interacting protein C-terminus-interacting protein (GIPC)-mediated trafficking of phosphatidylinositol 3-kinase (PI3K) regulates endothelial signaling and function. We demonstrate that endoglin interacts with the PI3K subunits p110α and p85 via GIPC to recruit and activate PI3K and Akt at the cell membrane. Opposing ligand-induced effects are observed in which TGF-β1 attenuates, whereas bone morphogenetic protein-9 enhances, endoglin/GIPC-mediated membrane scaffolding of PI3K and Akt to alter endothelial capillary tube stability in vitro. Moreover, we employ the first transgenic zebrafish model for endoglin to demonstrate that GIPC is a critical component of endoglin function during developmental angiogenesis in vivo. These studies define a novel non-Smad function for endoglin and GIPC in regulating endothelial cell function during angiogenesis.

Authors
Lee, NY; Golzio, C; Gatza, CE; Sharma, A; Katsanis, N; Blobe, GC
MLA Citation
Lee, NY, Golzio, C, Gatza, CE, Sharma, A, Katsanis, N, and Blobe, GC. "Endoglin regulates PI3-kinase/Akt trafficking and signaling to alter endothelial capillary stability during angiogenesis." Mol Biol Cell 23.13 (July 2012): 2412-2423.
PMID
22593212
Source
pubmed
Published In
Molecular Biology of the Cell
Volume
23
Issue
13
Publish Date
2012
Start Page
2412
End Page
2423
DOI
10.1091/mbc.E11-12-0993

OTX2 mutations contribute to the otocephaly-dysgnathia complex.

BACKGROUND: Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans. METHODS AND RESULTS: This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2, a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1, prrx1, and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity. CONCLUSION: Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.

Authors
Chassaing, N; Sorrentino, S; Davis, EE; Martin-Coignard, D; Iacovelli, A; Paznekas, W; Webb, BD; Faye-Petersen, O; Encha-Razavi, F; Lequeux, L; Vigouroux, A; Yesilyurt, A; Boyadjiev, SA; Kayserili, H; Loget, P; Carles, D; Sergi, C; Puvabanditsin, S; Chen, C-P; Etchevers, HC; Katsanis, N; Mercer, CL; Calvas, P; Jabs, EW
MLA Citation
Chassaing, N, Sorrentino, S, Davis, EE, Martin-Coignard, D, Iacovelli, A, Paznekas, W, Webb, BD, Faye-Petersen, O, Encha-Razavi, F, Lequeux, L, Vigouroux, A, Yesilyurt, A, Boyadjiev, SA, Kayserili, H, Loget, P, Carles, D, Sergi, C, Puvabanditsin, S, Chen, C-P, Etchevers, HC, Katsanis, N, Mercer, CL, Calvas, P, and Jabs, EW. "OTX2 mutations contribute to the otocephaly-dysgnathia complex." J Med Genet 49.6 (June 2012): 373-379.
PMID
22577225
Source
pubmed
Published In
Journal of medical genetics
Volume
49
Issue
6
Publish Date
2012
Start Page
373
End Page
379
DOI
10.1136/jmedgenet-2012-100892

The ciliopathies: a transitional model into systems biology of human genetic disease.

The last decade has witnessed an explosion in the identification of genes, mutations in which appear sufficient to cause clinical phenotypes in humans. This is especially true for disorders of ciliary dysfunction in which an excess of 50 causal loci are now known; this discovery was driven partly by an improved understanding of the protein composition of the cilium and the co-occurrence of clinical phenotypes associated with ciliary dysfunction. Despite this progress, the fundamental challenge of predicting phenotype and or clinical progression based on single locus information remains unsolved. Here, we explore how the combinatorial knowledge of allele quality and quantity, an improved understanding of the biological composition of the primary cilium, and the expanded appreciation of the subcellular roles of this organelle can be synthesized to generate improved models that can explain both causality but also variable penetrance and expressivity.

Authors
Davis, EE; Katsanis, N
MLA Citation
Davis, EE, and Katsanis, N. "The ciliopathies: a transitional model into systems biology of human genetic disease." Curr Opin Genet Dev 22.3 (June 2012): 290-303. (Review)
PMID
22632799
Source
pubmed
Published In
Current Opinion in Genetics and Development
Volume
22
Issue
3
Publish Date
2012
Start Page
290
End Page
303
DOI
10.1016/j.gde.2012.04.006

Prevalence and severity of fuchs corneal dystrophy in Tangier Island.

PURPOSE: To investigate the clinical and genetic features of late-onset Fuchs corneal dystrophy (FCD) on Tangier, an island in the Chesapeake Bay with an isolated population of approximately 500 individuals. DESIGN: Observational, cross-sectional study. METHODS: A total of 156 individuals born to inhabitants of Tangier Island volunteered to undergo ophthalmic evaluation. Medical history was ascertained prior to examination. All participants underwent anterior segment examination with slit-lamp biomicroscopy. Retroillumination photographs were acquired from affected individuals and the disease severity was compared with individuals from large families ascertained previously. Genomic DNA samples were investigated for the presence of the recently identified risk allele rs613872, an intronic variant of TCF4. RESULTS: Of the 148 examined individuals who were at least 30 years of age, 32 showed the classical symptoms of late-onset FCD (21.6%), providing a minimum prevalence of 11% among individuals over the age of 50 years. Severity was significantly lower compared to 51 cases from unlinked families, among individuals either 50 to 70 or above 70 years of age (P = .05 and P = .01, respectively). Retroillumination photography analyses were suggestive of mild severity when compared with the disease phenotype associated with FCD1- and FCD2-linked families. The rs613872 variant was associated with a higher affectation rate (P = .01), while the wild-type allele was correlated with a higher proportion of subclinical disease (P = .01). CONCLUSIONS: In this study population in Tangier, late-onset FCD manifests clinically with a mild phenotype and increased prevalence. The rs613872 variant correlates with increased affectation and a clinical disease phenotype.

Authors
Eghrari, AO; McGlumphy, EJ; Iliff, BW; Wang, J; Emmert, D; Riazuddin, SA; Katsanis, N; Gottsch, JD
MLA Citation
Eghrari, AO, McGlumphy, EJ, Iliff, BW, Wang, J, Emmert, D, Riazuddin, SA, Katsanis, N, and Gottsch, JD. "Prevalence and severity of fuchs corneal dystrophy in Tangier Island." Am J Ophthalmol 153.6 (June 2012): 1067-1072.
PMID
22321803
Source
pubmed
Published In
American Journal of Ophthalmology
Volume
153
Issue
6
Publish Date
2012
Start Page
1067
End Page
1072
DOI
10.1016/j.ajo.2011.11.033

KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.

Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.

Authors
Golzio, C; Willer, J; Talkowski, ME; Oh, EC; Taniguchi, Y; Jacquemont, S; Reymond, A; Sun, M; Sawa, A; Gusella, JF; Kamiya, A; Beckmann, JS; Katsanis, N
MLA Citation
Golzio, C, Willer, J, Talkowski, ME, Oh, EC, Taniguchi, Y, Jacquemont, S, Reymond, A, Sun, M, Sawa, A, Gusella, JF, Kamiya, A, Beckmann, JS, and Katsanis, N. "KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. (Published online)" Nature 485.7398 (May 16, 2012): 363-367.
PMID
22596160
Source
pubmed
Published In
Nature
Volume
485
Issue
7398
Publish Date
2012
Start Page
363
End Page
367
DOI
10.1038/nature11091

Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy.

Fuchs corneal dystrophy (FCD) is a genetic disorder of the corneal endothelium and is the most common cause of corneal transplantation in the United States. Previously, we mapped a late-onset FCD locus, FCD2, on chromosome 18q. Here, we present next-generation sequencing of all coding exons in the FCD2 critical interval in a multigenerational pedigree in which FCD segregates as an autosomal-dominant trait. We identified a missense change in LOXHD1, a gene causing progressive hearing loss in humans, as the sole variant capable of explaining the phenotype in this pedigree. We observed LOXHD1 mRNA in cultured human corneal endothelial cells, whereas antibody staining of both human and mouse corneas showed staining in the corneal epithelium and endothelium. Corneal sections of the original proband were stained for LOXHD1 and demonstrated a distinct increase in antibody punctate staining in the endothelium and Descemet membrane; punctate staining was absent from both normal corneas and FCD corneas negative for causal LOXHD1 mutations. Subsequent interrogation of a cohort of >200 sporadic affected individuals identified another 15 heterozygous missense mutations that were absent from >800 control chromosomes. Furthermore, in silico analyses predicted that these mutations reside on the surface of the protein and are likely to affect the protein's interface and protein-protein interactions. Finally, expression of the familial LOXHD1 mutant allele as well as two sporadic mutations in cells revealed prominent cytoplasmic aggregates reminiscent of the corneal phenotype. All together, our data implicate rare alleles in LOXHD1 in the pathogenesis of FCD and highlight how different mutations in the same locus can potentially produce diverse phenotypes.

Authors
Riazuddin, SA; Parker, DS; McGlumphy, EJ; Oh, EC; Iliff, BW; Schmedt, T; Jurkunas, U; Schleif, R; Katsanis, N; Gottsch, JD
MLA Citation
Riazuddin, SA, Parker, DS, McGlumphy, EJ, Oh, EC, Iliff, BW, Schmedt, T, Jurkunas, U, Schleif, R, Katsanis, N, and Gottsch, JD. "Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy." Am J Hum Genet 90.3 (March 9, 2012): 533-539.
PMID
22341973
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
90
Issue
3
Publish Date
2012
Start Page
533
End Page
539
DOI
10.1016/j.ajhg.2012.01.013

Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago, but its genetic cause has remained elusive. Here we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3. Our data identify the genetic cause of LGMD1D, suggest that its pathogenesis is mediated by defective chaperone function and highlight how mutations in a ubiquitously expressed gene can exert effects in a tissue-, isoform- and cellular compartment-specific manner.

Authors
Sarparanta, J; Jonson, PH; Golzio, C; Sandell, S; Luque, H; Screen, M; McDonald, K; Stajich, JM; Mahjneh, I; Vihola, A; Raheem, O; Penttilä, S; Lehtinen, S; Huovinen, S; Palmio, J; Tasca, G; Ricci, E; Hackman, P; Hauser, M; Katsanis, N; Udd, B
MLA Citation
Sarparanta, J, Jonson, PH, Golzio, C, Sandell, S, Luque, H, Screen, M, McDonald, K, Stajich, JM, Mahjneh, I, Vihola, A, Raheem, O, Penttilä, S, Lehtinen, S, Huovinen, S, Palmio, J, Tasca, G, Ricci, E, Hackman, P, Hauser, M, Katsanis, N, and Udd, B. "Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. (Published online)" Nat Genet 44.4 (February 26, 2012): 450-S2.
PMID
22366786
Source
pubmed
Published In
Nature Genetics
Volume
44
Issue
4
Publish Date
2012
Start Page
450
End Page
S2
DOI
10.1038/ng.1103

Evolutionarily assembled cis-regulatory module at a human ciliopathy locus.

Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.

Authors
Lee, JH; Silhavy, JL; Lee, JE; Al-Gazali, L; Thomas, S; Davis, EE; Bielas, SL; Hill, KJ; Iannicelli, M; Brancati, F; Gabriel, SB; Russ, C; Logan, CV; Sharif, SM; Bennett, CP; Abe, M; Hildebrandt, F; Diplas, BH; Attié-Bitach, T; Katsanis, N; Rajab, A; Koul, R; Sztriha, L; Waters, ER; Ferro-Novick, S; Woods, CG; Johnson, CA; Valente, EM; Zaki, MS; Gleeson, JG
MLA Citation
Lee, JH, Silhavy, JL, Lee, JE, Al-Gazali, L, Thomas, S, Davis, EE, Bielas, SL, Hill, KJ, Iannicelli, M, Brancati, F, Gabriel, SB, Russ, C, Logan, CV, Sharif, SM, Bennett, CP, Abe, M, Hildebrandt, F, Diplas, BH, Attié-Bitach, T, Katsanis, N, Rajab, A, Koul, R, Sztriha, L, Waters, ER, Ferro-Novick, S, Woods, CG, Johnson, CA, Valente, EM, Zaki, MS, and Gleeson, JG. "Evolutionarily assembled cis-regulatory module at a human ciliopathy locus." Science 335.6071 (February 24, 2012): 966-969.
PMID
22282472
Source
pubmed
Published In
Science
Volume
335
Issue
6071
Publish Date
2012
Start Page
966
End Page
969
DOI
10.1126/science.1213506

Cilia in vertebrate development and disease.

Through the combined study of model organisms, cell biology, cell signaling and medical genetics we have significantly increased our understanding of the structure and functions of the vertebrate cilium. This ancient organelle has now emerged as a crucial component of certain signaling and sensory perception pathways in both developmental and homeostatic contexts. Here, we provide a snapshot of the structure, function and distribution of the vertebrate cilium and of the pathologies that are associated with its dysfunction.

Authors
Oh, EC; Katsanis, N
MLA Citation
Oh, EC, and Katsanis, N. "Cilia in vertebrate development and disease." Development 139.3 (February 2012): 443-448. (Review)
PMID
22223675
Source
pubmed
Published In
Development (Cambridge)
Volume
139
Issue
3
Publish Date
2012
Start Page
443
End Page
448
DOI
10.1242/dev.050054

Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation.

Primary cilia are conserved organelles that play crucial roles as mechano- and chemosensors, as well as transducing signaling cascades. Consequently, ciliary dysfunction results in a broad range of phenotypes: the ciliopathies. Bardet-Biedl syndrome (BBS), a model ciliopathy, is caused by mutations in 16 known genes. However, the biochemical functions of the BBS proteins are not fully understood. Here we show that the BBS7 protein (localized in the centrosomes, basal bodies and cilia) probably has a nuclear role by virtue of the presence of a biologically confirmed nuclear export signal. Consistent with this observation, we show that BBS7 interacts physically with the polycomb group (PcG) member RNF2 and regulate its protein levels, probably through a proteasome-mediated mechanism. In addition, our data supports a similar role for other BBS proteins. Importantly, the interaction with this PcG member is biologically relevant because loss of BBS proteins leads to the aberrant expression of endogenous RNF2 targets in vivo, including several genes that are crucial for development and for cellular and tissue homeostasis. Our data indicate a hitherto unappreciated, direct role for the BBS proteins in transcriptional regulation and potentially expand the mechanistic spectrum that underpins the development of ciliary phenotypes in patients.

Authors
Gascue, C; Tan, PL; Cardenas-Rodriguez, M; Libisch, G; Fernandez-Calero, T; Liu, YP; Astrada, S; Robello, C; Naya, H; Katsanis, N; Badano, JL
MLA Citation
Gascue, C, Tan, PL, Cardenas-Rodriguez, M, Libisch, G, Fernandez-Calero, T, Liu, YP, Astrada, S, Robello, C, Naya, H, Katsanis, N, and Badano, JL. "Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation." J Cell Sci 125.Pt 2 (January 15, 2012): 362-375.
PMID
22302990
Source
pubmed
Published In
Journal of cell science
Volume
125
Issue
Pt 2
Publish Date
2012
Start Page
362
End Page
375
DOI
10.1242/jcs.089375

Exome and genome sequencing of neonates with neurodevelopmental disorders

Authors
Katsanis, N; Cotten, M; Angrist, M
MLA Citation
Katsanis, N, Cotten, M, and Angrist, M. "Exome and genome sequencing of neonates with neurodevelopmental disorders." Future Neurology 7.6 (2012): 655-658.
Source
scival
Published In
Future neurology
Volume
7
Issue
6
Publish Date
2012
Start Page
655
End Page
658
DOI
10.2217/fnl.12.74

Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes.

PURPOSE: To investigate the phenotypic variability of patients bearing the heterozygous R124H mutation in the TGFBI (transforming growth factor-beta-induced) gene that causes granular corneal dystrophy type 2 (GCD2). METHODS: We describe the phenotypic range of GCD2 heterozygotes for the common R124H mutation in TGFBI; seven with an extremely mild phenotype and six with an extremely severe phenotype. Detailed slit-lamp photographs of these patients were generated. All patients had no history of ocular surgery and were diagnosed as being heterozygous for GCD2 by DNA analysis from peripheral blood. Expression levels of transforming growth factor-beta-induced protein (TGFBIp) were compared among cultured corneal fibroblasts from ten normal donors. RESULTS: We report profound differences in the severity of the phenotype across our case series. Two patients with a mild phenotype were diagnosed as unaffected at presentation; however follow-up examinations revealed granular deposits. Importantly, we also observed familial clustering of phenotypic variance; five patients from two families with a mild phenotype showed a similarly mild phenotype within family members. Similarly, six patients from two families with severe phenotypes showed corneal deposits with similar patterns and severity within each distinct family, but distinct patterns between families. TGFBIp expressions from different donor derived cultured corneal fibroblasts were different between one another. CONCLUSIONS: GCD2 heterozygotes have extremely varied phenotypes between individual patients. However phenotypes were broadly consistent within families, suggesting that the observed variable expressivity might be regulated by other genetic factors that could influence the abundance of TGFBIp or the function of the pathway. From a clinical perspective, our data also highlighted that genetic analysis and meticulous slit-lamp examination in both eyes at multiple time intervals is necessary.

Authors
Han, KE; Choi, S-I; Chung, WS; Jung, SH; Katsanis, N; Kim, T-I; Kim, EK
MLA Citation
Han, KE, Choi, S-I, Chung, WS, Jung, SH, Katsanis, N, Kim, T-I, and Kim, EK. "Extremely varied phenotypes in granular corneal dystrophy type 2 heterozygotes." Mol Vis 18 (2012): 1755-1762.
PMID
22815629
Source
pubmed
Published In
Molecular vision
Volume
18
Publish Date
2012
Start Page
1755
End Page
1762

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone.

Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.

Authors
Huang, L; Szymanska, K; Jensen, VL; Janecke, AR; Innes, AM; Davis, EE; Frosk, P; Li, C; Willer, JR; Chodirker, BN; Greenberg, CR; McLeod, DR; Bernier, FP; Chudley, AE; Müller, T; Shboul, M; Logan, CV; Loucks, CM; Beaulieu, CL; Bowie, RV; Bell, SM; Adkins, J; Zuniga, FI; Ross, KD; Wang, J; Ban, MR; Becker, C; Nürnberg, P; Douglas, S; Craft, CM; Akimenko, M-A; Hegele, RA; Ober, C; Utermann, G; Bolz, HJ; Bulman, DE; Katsanis, N; Blacque, OE; Doherty, D; Parboosingh, JS; Leroux, MR; Johnson, CA et al.
MLA Citation
Huang, L, Szymanska, K, Jensen, VL, Janecke, AR, Innes, AM, Davis, EE, Frosk, P, Li, C, Willer, JR, Chodirker, BN, Greenberg, CR, McLeod, DR, Bernier, FP, Chudley, AE, Müller, T, Shboul, M, Logan, CV, Loucks, CM, Beaulieu, CL, Bowie, RV, Bell, SM, Adkins, J, Zuniga, FI, Ross, KD, Wang, J, Ban, MR, Becker, C, Nürnberg, P, Douglas, S, Craft, CM, Akimenko, M-A, Hegele, RA, Ober, C, Utermann, G, Bolz, HJ, Bulman, DE, Katsanis, N, Blacque, OE, Doherty, D, Parboosingh, JS, Leroux, MR, and Johnson, CA et al. "TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone." Am J Hum Genet 89.6 (December 9, 2011): 713-730.
PMID
22152675
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
89
Issue
6
Publish Date
2011
Start Page
713
End Page
730
DOI
10.1016/j.ajhg.2011.11.005

A rare penetrant mutation in CFH confers high risk of age-related macular degeneration.

Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)(1-4) and the intronic rs1410996 SNP(5,6), explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and knowledge of the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high-throughput sequencing to discover a rare, high-risk CFH haplotype with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it abrogates C-terminal ligand binding(7,8). Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, P = 7.0 × 10(-6)) and an association with a 6-year-earlier onset of disease (P = 2.3 × 10(-6)). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.

Authors
Raychaudhuri, S; Iartchouk, O; Chin, K; Tan, PL; Tai, AK; Ripke, S; Gowrisankar, S; Vemuri, S; Montgomery, K; Yu, Y; Reynolds, R; Zack, DJ; Campochiaro, B; Campochiaro, P; Katsanis, N; Daly, MJ; Seddon, JM
MLA Citation
Raychaudhuri, S, Iartchouk, O, Chin, K, Tan, PL, Tai, AK, Ripke, S, Gowrisankar, S, Vemuri, S, Montgomery, K, Yu, Y, Reynolds, R, Zack, DJ, Campochiaro, B, Campochiaro, P, Katsanis, N, Daly, MJ, and Seddon, JM. "A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. (Published online)" Nat Genet 43.12 (October 23, 2011): 1232-1236.
PMID
22019782
Source
pubmed
Published In
Nature Genetics
Volume
43
Issue
12
Publish Date
2011
Start Page
1232
End Page
1236
DOI
10.1038/ng.976

Ectopic overexpression of Sonic Hedgehog (Shh) induces stromal expansion and metaplasia in the adult murine pancreas.

Ligand-dependent activation of the Hedgehog (Hh) signaling pathway has been implicated in both tumor initiation and metastasis of pancreatic ductal adenocarcinoma (PDAC). Prior studies in genetically engineered mouse models (GEMMs) have assessed the role of Hh signaling by cell autonomous expression of a constitutively active Gli2 within epithelial cells. On the contrary, aberrant pathway reactivation in the human exocrine pancreas occurs principally as a consequence of Sonic Hh ligand (Shh) overexpression from epithelial cells. To recapitulate the cognate pathophysiology of Hh signaling observed in the human pancreas, we examined GEMM where Hh ligand is conditionally overexpressed within the mature exocrine pancreas using a tamoxifen-inducible Elastase-Cre promoter (Ela-CreERT2;LSL-mShh). We also facilitated potential cell autonomous epithelial responsiveness to secreted Hh ligand by generating compound transgenic mice with concomitant expression of the Hh receptor Smoothened (Ela-CreERT2;LSL-mShh;LSL-mSmo). Of interest, none of these mice developed intraductal precursor lesions or PDAC during the follow-up period of up to 12 months after tamoxifen induction. Instead, all animals demonstrated marked expansion of stromal cells, consistent with the previously described epithelial-to-stromal paracrine Hh signaling. Hh responsiveness was mirrored by the expression of primary cilia within the expanded mesenchymal compartment and the absence within mature acinar cells. In the absence of cooperating mutations, Hh ligand overexpression in the mature exocrine pancreas is insufficient to induce neoplasia, even when epithelial cells coexpress the Smo receptor. This autochthonous model serves as a platform for studying epithelial stromal interactions in pancreatic carcinogenesis.

Authors
Fendrich, V; Oh, E; Bang, S; Karikari, C; Ottenhof, N; Bisht, S; Lauth, M; Brossart, P; Katsanis, N; Maitra, A; Feldmann, G
MLA Citation
Fendrich, V, Oh, E, Bang, S, Karikari, C, Ottenhof, N, Bisht, S, Lauth, M, Brossart, P, Katsanis, N, Maitra, A, and Feldmann, G. "Ectopic overexpression of Sonic Hedgehog (Shh) induces stromal expansion and metaplasia in the adult murine pancreas." Neoplasia 13.10 (October 2011): 923-930.
PMID
22028618
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
13
Issue
10
Publish Date
2011
Start Page
923
End Page
930

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Authors
Yu, Y; Bhangale, TR; Fagerness, J; Ripke, S; Thorleifsson, G; Tan, PL; Souied, EH; Richardson, AJ; Merriam, JE; Buitendijk, GHS; Reynolds, R; Raychaudhuri, S; Chin, KA; Sobrin, L; Evangelou, E; Lee, PH; Lee, AY; Leveziel, N; Zack, DJ; Campochiaro, B; Campochiaro, P; Smith, RT; Barile, GR; Guymer, RH; Hogg, R; Chakravarthy, U; Robman, LD; Gustafsson, O; Sigurdsson, H; Ortmann, W; Behrens, TW; Stefansson, K; Uitterlinden, AG; van Duijn, CM; Vingerling, JR; Klaver, CCW; Allikmets, R; Brantley, MA et al.
MLA Citation
Yu, Y, Bhangale, TR, Fagerness, J, Ripke, S, Thorleifsson, G, Tan, PL, Souied, EH, Richardson, AJ, Merriam, JE, Buitendijk, GHS, Reynolds, R, Raychaudhuri, S, Chin, KA, Sobrin, L, Evangelou, E, Lee, PH, Lee, AY, Leveziel, N, Zack, DJ, Campochiaro, B, Campochiaro, P, Smith, RT, Barile, GR, Guymer, RH, Hogg, R, Chakravarthy, U, Robman, LD, Gustafsson, O, Sigurdsson, H, Ortmann, W, Behrens, TW, Stefansson, K, Uitterlinden, AG, van Duijn, CM, Vingerling, JR, Klaver, CCW, Allikmets, R, and Brantley, MA et al. "Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration." Hum Mol Genet 20.18 (September 15, 2011): 3699-3709.
PMID
21665990
Source
pubmed
Published In
Human Molecular Genetics
Volume
20
Issue
18
Publish Date
2011
Start Page
3699
End Page
3709
DOI
10.1093/hmg/ddr270

Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly.

The ciliopathies are an expanding group of disorders caused by mutations in genes implicated in the biogenesis and function of primary cilia. Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by progressive retinal degeneration, obesity, polydactyly, cognitive impairment, kidney anomalies and hypogonadism. Mutations in SDCCAG8(NPHP10) were described recently in patients with nephronophthisis and retinal degeneration (Senior-Loken syndrome; SLS). Given the phenotypic and genetic overlap between known ciliopathy genes, we hypothesized that mutations in SDCCAG8 might also contribute alleles to more severe, multisystemic ciliopathies. We performed genetic and phenotypic analyses of 2 independent BBS cohorts. Subsequent to mutation screening, we made a detailed phenotypic analysis of 5 families mutated for SDCCAG8 (3 homozygous and 2 compound heterozygous mutations) and conducted statistical analyses across both cohorts to examine possible phenotype-genotype correlations with mutations at this locus. All patients with mutations in SDCCAG8 fulfilled the diagnostic criteria for BBS (retinal degeneration, obesity, cognitive defects, renal failure, hypogonadism). Interestingly, none of the patients with primary SDCCAG8 mutations had polydactyly, a frequent but not obligatory BBS feature. In contrast, the same patients displayed early-onset renal failure, obesity, as well as recurrent pulmonary and ENT infections. Comparison of the phenotypes of these families with our entire BBS cohort indicated that renal impairment and absent polydactyly correlated significantly with causal SDCCAG8 mutations. Thus, SDCCAG8 mutations are sufficient to cause BBS in 1-2% of our combined cohorts, and define this gene as the sixteenth BBS locus (BBS16). The absence of polydactyly and the concomitant, apparently fully penetrant association with early kidney failure represents the first significant genotype-phenotype correlation in BBS that potentially represents an indicator for phenotype-driven priority screening and informs specific patient management.

Authors
Schaefer, E; Zaloszyc, A; Lauer, J; Durand, M; Stutzmann, F; Perdomo-Trujillo, Y; Redin, C; Bennouna Greene, V; Toutain, A; Perrin, L; Gérard, M; Caillard, S; Bei, X; Lewis, RA; Christmann, D; Letsch, J; Kribs, M; Mutter, C; Muller, J; Stoetzel, C; Fischbach, M; Marion, V; Katsanis, N; Dollfus, H
MLA Citation
Schaefer, E, Zaloszyc, A, Lauer, J, Durand, M, Stutzmann, F, Perdomo-Trujillo, Y, Redin, C, Bennouna Greene, V, Toutain, A, Perrin, L, Gérard, M, Caillard, S, Bei, X, Lewis, RA, Christmann, D, Letsch, J, Kribs, M, Mutter, C, Muller, J, Stoetzel, C, Fischbach, M, Marion, V, Katsanis, N, and Dollfus, H. "Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly." Mol Syndromol 1.6 (September 2011): 273-281.
PMID
22190896
Source
pubmed
Published In
Molecular Syndromology
Volume
1
Issue
6
Publish Date
2011
Start Page
273
End Page
281
DOI
10.1159/000331268

Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms.

Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies. Such grouping is underscored by two major observations: the fact that genes encoding ciliary proteins can contribute causal and modifying mutations across several clinically discrete ciliopathies, and the emerging realization that an understanding of the clinical pathology of one ciliopathy can provide valuable insight into the pathomechanism of renal cyst formation elsewhere in the ciliopathy spectrum. In this review, we discuss and attempt to stratify the different lines of proposed cilia-driven mechanisms for cystogenesis, ranging from mechano- and chemo-sensation, to cell shape and polarization, to the transduction of a variety of signaling cascades. We evaluate both common trends and differences across the models and discuss how each proposed mechanism can contribute to the development of novel therapeutic paradigms.

Authors
Gascue, C; Katsanis, N; Badano, JL
MLA Citation
Gascue, C, Katsanis, N, and Badano, JL. "Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms." Pediatr Nephrol 26.8 (August 2011): 1181-1195. (Review)
PMID
21113628
Source
pubmed
Published In
Pediatric Nephrology
Volume
26
Issue
8
Publish Date
2011
Start Page
1181
End Page
1195
DOI
10.1007/s00467-010-1697-5

Neuroscience: Imprinting in the brain.

Authors
Oh, EC; Katsanis, N
MLA Citation
Oh, EC, and Katsanis, N. "Neuroscience: Imprinting in the brain. (Published online)" Nature 475.7356 (July 20, 2011): 299-300.
PMID
21776070
Source
pubmed
Published In
Nature
Volume
475
Issue
7356
Publish Date
2011
Start Page
299
End Page
300
DOI
10.1038/475299a

Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes.

PURPOSE: Bardet-Biedl syndrome (BBS) is genetically heterogeneous with 15 BBS genes currently identified, accounting for approximately 70% of cases. The aim of our study was to define further the spectrum of BBS mutations in a cohort of 44 European-derived American, 8 Tunisian, 1 Arabic, and 2 Pakistani families (55 families in total) with BBS. METHODS: A total of 142 exons of the first 12 BBS-causing genes were screened by dideoxy sequencing. Cases in which no mutations were found were then screened for BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, and INPP5E. RESULTS: Forty-three mutations, including 8 frameshift mutations, 10 nonsense mutations, 4 splice site mutations, 1 deletion, and 20 potentially or probably pathogenic missense variations, were identified in 46 of the 55 families studied (84%). Of these, 21 (2 frameshift mutations, 4 nonsense mutations, 4 splice site mutations, 1 deletion, and 10 missense variations) were novel. The molecular genetic findings raised the possibility of triallelic inheritance in 7 Caucasian families, 1 Arabian family, and 1 Tunisian patient. No mutations were detected for BBS4, BBS11, BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, or INPP5E. CONCLUSIONS: This mutational analysis extends the spectrum of known BBS mutations. Identification of 21 novel mutations highlights the genetic heterogeneity of this disorder. Differences in European and Tunisian patients, including the high frequency of the M390R mutation in Europeans, emphasize the population specificity of BBS mutations with potential diagnostic implications. The existence of some BBS cases without mutations in any currently identified BBS genes suggests further genetic heterogeneity.

Authors
Chen, J; Smaoui, N; Hammer, MBH; Jiao, X; Riazuddin, SA; Harper, S; Katsanis, N; Riazuddin, S; Chaabouni, H; Berson, EL; Hejtmancik, JF
MLA Citation
Chen, J, Smaoui, N, Hammer, MBH, Jiao, X, Riazuddin, SA, Harper, S, Katsanis, N, Riazuddin, S, Chaabouni, H, Berson, EL, and Hejtmancik, JF. "Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes. (Published online)" Invest Ophthalmol Vis Sci 52.8 (July 18, 2011): 5317-5324.
PMID
21642631
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
52
Issue
8
Publish Date
2011
Start Page
5317
End Page
5324
DOI
10.1167/iovs.11-7554

Disruption of a ciliary B9 protein complex causes Meckel syndrome.

Nearly every ciliated organism possesses three B9 domain-containing proteins: MKS1, B9D1, and B9D2. Mutations in human MKS1 cause Meckel syndrome (MKS), a severe ciliopathy characterized by occipital encephalocele, liver ductal plate malformations, polydactyly, and kidney cysts. Mouse mutations in either Mks1 or B9d2 compromise ciliogenesis and result in phenotypes similar to those of MKS. Given the importance of these two B9 proteins to ciliogenesis, we examined the role of the third B9 protein, B9d1. Mice lacking B9d1 displayed polydactyly, kidney cysts, ductal plate malformations, and abnormal patterning of the neural tube, concomitant with compromised ciliogenesis, ciliary protein localization, and Hedgehog (Hh) signal transduction. These data prompted us to screen MKS patients for mutations in B9D1 and B9D2. We identified a homozygous c.301A>C (p.Ser101Arg) B9D2 mutation that segregates with MKS, affects an evolutionarily conserved residue, and is absent from controls. Unlike wild-type B9D2 mRNA, the p.Ser101Arg mutation failed to rescue zebrafish phenotypes induced by the suppression of b9d2. With coimmunoprecipitation and mass spectrometric analyses, we found that Mks1, B9d1, and B9d2 interact physically, but that the p.Ser101Arg mutation abrogates the ability of B9d2 to interact with Mks1, further suggesting that the mutation compromises B9d2 function. Our data indicate that B9d1 is required for normal Hh signaling, ciliogenesis, and ciliary protein localization and that B9d1 and B9d2 are essential components of a B9 protein complex, disruption of which causes MKS.

Authors
Dowdle, WE; Robinson, JF; Kneist, A; Sirerol-Piquer, MS; Frints, SGM; Corbit, KC; Zaghloul, NA; van Lijnschoten, G; Mulders, L; Verver, DE; Zerres, K; Reed, RR; Attié-Bitach, T; Johnson, CA; García-Verdugo, JM; Katsanis, N; Bergmann, C; Reiter, JF
MLA Citation
Dowdle, WE, Robinson, JF, Kneist, A, Sirerol-Piquer, MS, Frints, SGM, Corbit, KC, Zaghloul, NA, van Lijnschoten, G, Mulders, L, Verver, DE, Zerres, K, Reed, RR, Attié-Bitach, T, Johnson, CA, García-Verdugo, JM, Katsanis, N, Bergmann, C, and Reiter, JF. "Disruption of a ciliary B9 protein complex causes Meckel syndrome." Am J Hum Genet 89.1 (July 15, 2011): 94-110.
PMID
21763481
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
89
Issue
1
Publish Date
2011
Start Page
94
End Page
110
DOI
10.1016/j.ajhg.2011.06.003

Understanding cargo specificity in intraflagellar transport.

Authors
Parker, DS; Katsanis, N
MLA Citation
Parker, DS, and Katsanis, N. "Understanding cargo specificity in intraflagellar transport. (Published online)" EMBO J 30.13 (July 6, 2011): 2518-2519.
PMID
21731048
Source
pubmed
Published In
EMBO Journal
Volume
30
Issue
13
Publish Date
2011
Start Page
2518
End Page
2519
DOI
10.1038/emboj.2011.196

A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.

Mutations affecting ciliary components cause ciliopathies. As described here, we investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel and Joubert syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2 and Cc2d2a. Components of this complex co-localize at the transition zone, a region between the basal body and ciliary axoneme. Like Tctn1, loss of Tctn2, Tmem67 or Cc2d2a causes tissue-specific defects in ciliogenesis and ciliary membrane composition. Consistent with a shared function for complex components, we identified a mutation in TCTN1 that causes Joubert syndrome. Thus, a transition zone complex of Meckel and Joubert syndrome proteins regulates ciliary assembly and trafficking, suggesting that transition zone dysfunction is the cause of these ciliopathies.

Authors
Garcia-Gonzalo, FR; Corbit, KC; Sirerol-Piquer, MS; Ramaswami, G; Otto, EA; Noriega, TR; Seol, AD; Robinson, JF; Bennett, CL; Josifova, DJ; García-Verdugo, JM; Katsanis, N; Hildebrandt, F; Reiter, JF
MLA Citation
Garcia-Gonzalo, FR, Corbit, KC, Sirerol-Piquer, MS, Ramaswami, G, Otto, EA, Noriega, TR, Seol, AD, Robinson, JF, Bennett, CL, Josifova, DJ, García-Verdugo, JM, Katsanis, N, Hildebrandt, F, and Reiter, JF. "A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. (Published online)" Nat Genet 43.8 (July 3, 2011): 776-784.
PMID
21725307
Source
pubmed
Published In
Nature Genetics
Volume
43
Issue
8
Publish Date
2011
Start Page
776
End Page
784
DOI
10.1038/ng.891

Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting.

Bardet-Biedl syndrome (BBS) is a pleiotropic, heterogeneous human disease whose etiology lies primarily in dysfunctional basal bodies and/or cilia. Both BBS patients and several BBS mouse models exhibit impaired olfactory function. To explore the nature of olfactory defects in BBS, a genetic ablation of the mouse Bbs8 gene that incorporates a fluorescent reporter protein was created. The endogenous BBS8 protein and reporter are particularly abundant in olfactory sensory neurons (OSNs), and specific BBS8 antibodies reveal staining in the dendritic knob in a shell-like structure that surrounds the basal bodies. Bbs8-null mice have reduced olfactory responses to a number of odorants, and immunohistochemical analyses reveal a near-complete loss of cilia from OSNs and mislocalization of proteins normally enriched in cilia. To visualize altered protein localization in OSNs, we generated a SLP3(eGFP) knock-in mouse and imaged the apical epithelium, including dendritic knobs and proximal cilia, in ex vivo tissue preparations. Additionally, protein reagents that reflect the characteristic neuronal activity of each OSN revealed altered activity in Bbs8-null cells. In addition to previously known defects at the ciliary border, we also observed aberrant targeting of OSN axons to the olfactory bulb; axons expressing the same receptor display reduced fasciculation and project to multiple targets in the olfactory bulb. We suggest that loss of BBS8 leads to a dramatic and variable reduction in cilia, the essential signaling platform for olfaction, which alters the uniformity of responses in populations of OSNs expressing the same receptor, thereby contributing to the observed axon-targeting defects.

Authors
Tadenev, ALD; Kulaga, HM; May-Simera, HL; Kelley, MW; Katsanis, N; Reed, RR
MLA Citation
Tadenev, ALD, Kulaga, HM, May-Simera, HL, Kelley, MW, Katsanis, N, and Reed, RR. "Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting." Proc Natl Acad Sci U S A 108.25 (June 21, 2011): 10320-10325.
PMID
21646512
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
25
Publish Date
2011
Start Page
10320
End Page
10325
DOI
10.1073/pnas.1016531108

KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

Authors
Putoux, A; Thomas, S; Coene, KLM; Davis, EE; Alanay, Y; Ogur, G; Uz, E; Buzas, D; Gomes, C; Patrier, S; Bennett, CL; Elkhartoufi, N; Frison, M-HS; Rigonnot, L; Joyé, N; Pruvost, S; Utine, GE; Boduroglu, K; Nitschke, P; Fertitta, L; Thauvin-Robinet, C; Munnich, A; Cormier-Daire, V; Hennekam, R; Colin, E; Akarsu, NA; Bole-Feysot, C; Cagnard, N; Schmitt, A; Goudin, N; Lyonnet, S; Encha-Razavi, F; Siffroi, J-P; Winey, M; Katsanis, N; Gonzales, M; Vekemans, M; Beales, PL; Attié-Bitach, T
MLA Citation
Putoux, A, Thomas, S, Coene, KLM, Davis, EE, Alanay, Y, Ogur, G, Uz, E, Buzas, D, Gomes, C, Patrier, S, Bennett, CL, Elkhartoufi, N, Frison, M-HS, Rigonnot, L, Joyé, N, Pruvost, S, Utine, GE, Boduroglu, K, Nitschke, P, Fertitta, L, Thauvin-Robinet, C, Munnich, A, Cormier-Daire, V, Hennekam, R, Colin, E, Akarsu, NA, Bole-Feysot, C, Cagnard, N, Schmitt, A, Goudin, N, Lyonnet, S, Encha-Razavi, F, Siffroi, J-P, Winey, M, Katsanis, N, Gonzales, M, Vekemans, M, Beales, PL, and Attié-Bitach, T. "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes." Nat Genet 43.6 (June 2011): 601-606.
PMID
21552264
Source
pubmed
Published In
Nature Genetics
Volume
43
Issue
6
Publish Date
2011
Start Page
601
End Page
606
DOI
10.1038/ng.826

DISC1-dependent switch from progenitor proliferation to migration in the developing cortex.

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling via an interaction with GSK3β, whereas specific phosphorylation at serine 710 (S710) triggers the recruitment of Bardet-Biedl syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.

Authors
Ishizuka, K; Kamiya, A; Oh, EC; Kanki, H; Seshadri, S; Robinson, JF; Murdoch, H; Dunlop, AJ; Kubo, K-I; Furukori, K; Huang, B; Zeledon, M; Hayashi-Takagi, A; Okano, H; Nakajima, K; Houslay, MD; Katsanis, N; Sawa, A
MLA Citation
Ishizuka, K, Kamiya, A, Oh, EC, Kanki, H, Seshadri, S, Robinson, JF, Murdoch, H, Dunlop, AJ, Kubo, K-I, Furukori, K, Huang, B, Zeledon, M, Hayashi-Takagi, A, Okano, H, Nakajima, K, Houslay, MD, Katsanis, N, and Sawa, A. "DISC1-dependent switch from progenitor proliferation to migration in the developing cortex." Nature 473.7345 (May 5, 2011): 92-96.
PMID
21471969
Source
pubmed
Published In
Nature
Volume
473
Issue
7345
Publish Date
2011
Start Page
92
End Page
96
DOI
10.1038/nature09859

Ciliopathies.

Authors
Hildebrandt, F; Benzing, T; Katsanis, N
MLA Citation
Hildebrandt, F, Benzing, T, and Katsanis, N. "Ciliopathies." N Engl J Med 364.16 (April 21, 2011): 1533-1543. (Review)
PMID
21506742
Source
pubmed
Published In
The New England journal of medicine
Volume
364
Issue
16
Publish Date
2011
Start Page
1533
End Page
1543
DOI
10.1056/NEJMra1010172

Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10(-35); ADD: P = 7.48×10(-30); REC: P = 5.27×10(-6)). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.

Authors
Li, Y-J; Minear, MA; Rimmler, J; Zhao, B; Balajonda, E; Hauser, MA; Allingham, RR; Eghrari, AO; Riazuddin, SA; Katsanis, N; Gottsch, JD; Gregory, SG; Klintworth, GK; Afshari, NA
MLA Citation
Li, Y-J, Minear, MA, Rimmler, J, Zhao, B, Balajonda, E, Hauser, MA, Allingham, RR, Eghrari, AO, Riazuddin, SA, Katsanis, N, Gottsch, JD, Gregory, SG, Klintworth, GK, and Afshari, NA. "Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. (Published online)" PLoS One 6.4 (April 20, 2011): e18044-.
PMID
21533127
Source
pubmed
Published In
PloS one
Volume
6
Issue
4
Publish Date
2011
Start Page
e18044
DOI
10.1371/journal.pone.0018044

Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.

PURPOSE: Fuchs corneal dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, rs613872, an intronic variation of TCF4 associated with late-onset FCD, was reported. The present study was undertaken to examine this association in our cohort of FCD patients, to assess the significance of this finding, and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus. METHODS: The authors recruited 170 patients with late-onset FCD and 180 age-matched controls. Blood samples were collected, and genomic DNA was extracted. A panel of nine SNPs spanning the entire TCF4 locus was genotyped both on this cohort and on three previously reported FCD2-linked families. The association of an individual SNP with late-onset FCD was evaluated with the Fisher exact test, and the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected persons. RESULTS: The risk allele G of rs613872 is associated significantly with late-onset FCD (odds ratio, 4.2; P = 4.28 x 10⁻¹⁵) and was present in male and female affected persons without any sex bias, replicating recent findings, though the authors found no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not cosegregate with the disease phenotype in any of the three FCD2-linked families. The authors did not identify any pathogenic variants in the coding region of TCF4. CONCLUSIONS: The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown.

Authors
Riazuddin, SA; McGlumphy, EJ; Yeo, WS; Wang, J; Katsanis, N; Gottsch, JD
MLA Citation
Riazuddin, SA, McGlumphy, EJ, Yeo, WS, Wang, J, Katsanis, N, and Gottsch, JD. "Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus. (Published online)" Invest Ophthalmol Vis Sci 52.5 (April 2011): 2825-2829.
PMID
21245398
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
52
Issue
5
Publish Date
2011
Start Page
2825
End Page
2829
DOI
10.1167/iovs.10-6497

Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry.

The primary cilium is an antenna-like organelle that is dynamically regulated during the cell cycle. Ciliogenesis is initiated as cells enter quiescence, whereas resorption of the cilium precedes mitosis. The mechanisms coordinating ciliogenesis with the cell cycle are unknown. Here we identify the centrosomal protein Nde1 (nuclear distribution gene E homologue 1) as a negative regulator of ciliary length. Nde1 is expressed at high levels in mitosis, low levels in quiescence and localizes at the mother centriole, which nucleates the primary cilium. Cells depleted of Nde1 have longer cilia and a delay in cell cycle re-entry that correlates with ciliary length. Knockdown of Nde1 in zebrafish embryos results in increased ciliary length, suppression of cell division, reduction of the number of cells forming the Kupffer's vesicle and left-right patterning defects. These data suggest that Nde1 is an integral component of a network coordinating ciliary length with cell cycle progression and have implications for understanding the transition from a quiescent to a proliferative state.

Authors
Kim, S; Zaghloul, NA; Bubenshchikova, E; Oh, EC; Rankin, S; Katsanis, N; Obara, T; Tsiokas, L
MLA Citation
Kim, S, Zaghloul, NA, Bubenshchikova, E, Oh, EC, Rankin, S, Katsanis, N, Obara, T, and Tsiokas, L. "Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry." Nat Cell Biol 13.4 (April 2011): 351-360.
PMID
21394081
Source
pubmed
Published In
Nature Cell Biology
Volume
13
Issue
4
Publish Date
2011
Start Page
351
End Page
360
DOI
10.1038/ncb2183

Arrayed primer extension technology simplifies mutation detection in Bardet-Biedl and Alström syndrome.

Bardet-Biedl syndrome (BBS; OMIM no. 209 900) and Alström syndrome (ALMS; OMIM no. 203 800) are rare, multisystem genetic disorders showing both a highly variable phenotype and considerable phenotypic overlap; they are included in the emerging group of diseases called ciliopathies. The genetic heterogeneity of BBS with 14 causal genes described to date, serves to further complicate mutational analysis. The development of the BBS-ALMS array which detects known mutations in these genes has allowed us to detect at least one mutation in 40.5% of BBS families and in 26.7% of ALMS families validating this as an efficient and cost-effective first pass screening modality. Furthermore, using this method, we found two BBS families segregating three BBS alleles further supporting oligogenicity or modifier roles for additional mutations. We did not observe more than two mutations in any ALMS family.

Authors
Pereiro, I; Hoskins, BE; Marshall, JD; Collin, GB; Naggert, JK; Piñeiro-Gallego, T; Oitmaa, E; Katsanis, N; Valverde, D; Beales, PL
MLA Citation
Pereiro, I, Hoskins, BE, Marshall, JD, Collin, GB, Naggert, JK, Piñeiro-Gallego, T, Oitmaa, E, Katsanis, N, Valverde, D, and Beales, PL. "Arrayed primer extension technology simplifies mutation detection in Bardet-Biedl and Alström syndrome." Eur J Hum Genet 19.4 (April 2011): 485-488.
PMID
21157496
Source
pubmed
Published In
European Journal of Human Genetics
Volume
19
Issue
4
Publish Date
2011
Start Page
485
End Page
488
DOI
10.1038/ejhg.2010.207

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum.

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.

Authors
Davis, EE; Zhang, Q; Liu, Q; Diplas, BH; Davey, LM; Hartley, J; Stoetzel, C; Szymanska, K; Ramaswami, G; Logan, CV; Muzny, DM; Young, AC; Wheeler, DA; Cruz, P; Morgan, M; Lewis, LR; Cherukuri, P; Maskeri, B; Hansen, NF; Mullikin, JC; Blakesley, RW; Bouffard, GG; NISC Comparative Sequencing Program, ; Gyapay, G; Rieger, S; Tönshoff, B; Kern, I; Soliman, NA; Neuhaus, TJ; Swoboda, KJ; Kayserili, H; Gallagher, TE; Lewis, RA; Bergmann, C; Otto, EA; Saunier, S; Scambler, PJ; Beales, PL; Gleeson, JG et al.
MLA Citation
Davis, EE, Zhang, Q, Liu, Q, Diplas, BH, Davey, LM, Hartley, J, Stoetzel, C, Szymanska, K, Ramaswami, G, Logan, CV, Muzny, DM, Young, AC, Wheeler, DA, Cruz, P, Morgan, M, Lewis, LR, Cherukuri, P, Maskeri, B, Hansen, NF, Mullikin, JC, Blakesley, RW, Bouffard, GG, NISC Comparative Sequencing Program, , Gyapay, G, Rieger, S, Tönshoff, B, Kern, I, Soliman, NA, Neuhaus, TJ, Swoboda, KJ, Kayserili, H, Gallagher, TE, Lewis, RA, Bergmann, C, Otto, EA, Saunier, S, Scambler, PJ, Beales, PL, and Gleeson, JG et al. "TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum." Nat Genet 43.3 (March 2011): 189-196.
PMID
21258341
Source
pubmed
Published In
Nature Genetics
Volume
43
Issue
3
Publish Date
2011
Start Page
189
End Page
196
DOI
10.1038/ng.756

CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs.

Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.

Authors
Merveille, A-C; Davis, EE; Becker-Heck, A; Legendre, M; Amirav, I; Bataille, G; Belmont, J; Beydon, N; Billen, F; Clément, A; Clercx, C; Coste, A; Crosbie, R; de Blic, J; Deleuze, S; Duquesnoy, P; Escalier, D; Escudier, E; Fliegauf, M; Horvath, J; Hill, K; Jorissen, M; Just, J; Kispert, A; Lathrop, M; Loges, NT; Marthin, JK; Momozawa, Y; Montantin, G; Nielsen, KG; Olbrich, H; Papon, J-F; Rayet, I; Roger, G; Schmidts, M; Tenreiro, H; Towbin, JA; Zelenika, D; Zentgraf, H; Georges, M et al.
MLA Citation
Merveille, A-C, Davis, EE, Becker-Heck, A, Legendre, M, Amirav, I, Bataille, G, Belmont, J, Beydon, N, Billen, F, Clément, A, Clercx, C, Coste, A, Crosbie, R, de Blic, J, Deleuze, S, Duquesnoy, P, Escalier, D, Escudier, E, Fliegauf, M, Horvath, J, Hill, K, Jorissen, M, Just, J, Kispert, A, Lathrop, M, Loges, NT, Marthin, JK, Momozawa, Y, Montantin, G, Nielsen, KG, Olbrich, H, Papon, J-F, Rayet, I, Roger, G, Schmidts, M, Tenreiro, H, Towbin, JA, Zelenika, D, Zentgraf, H, and Georges, M et al. "CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs." Nat Genet 43.1 (January 2011): 72-78.
PMID
21131972
Source
pubmed
Published In
Nature Genetics
Volume
43
Issue
1
Publish Date
2011
Start Page
72
End Page
78
DOI
10.1038/ng.726

Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals.

Bardet-Biedl syndrome (BBS) is a rare, primarily autosomal-recessive ciliopathy. The phenotype of this pleiotropic disease includes retinitis pigmentosa, postaxial polydactyly, truncal obesity, learning disabilities, hypogonadism and renal anomalies, among others. To date, mutations in 15 genes (BBS1-BBS14, SDCCAG8) have been described to cause BBS. The broad genetic locus heterogeneity renders mutation screening time-consuming and expensive. We applied a strategy of DNA pooling and subsequent massively parallel resequencing (MPR) to screen individuals affected with BBS from 105 families for mutations in 12 known BBS genes. DNA was pooled in 5 pools of 21 individuals each. All 132 coding exons of BBS1-BBS12 were amplified by conventional PCR. Subsequent MPR was performed on an Illumina Genome Analyzer II™ platform. Following mutation identification, the mutation carrier was assigned by CEL I endonuclease heteroduplex screening and confirmed by Sanger sequencing. In 29 out of 105 individuals (28%), both mutated alleles were identified in 10 different BBS genes. A total of 35 different disease-causing mutations were confirmed, of which 18 mutations were novel. In 12 additional families, a total of 12 different single heterozygous changes of uncertain pathogenicity were found. Thus, DNA pooling combined with MPR offers a valuable strategy for mutation analysis of large patient cohorts, especially in genetically heterogeneous diseases such as BBS.

Authors
Janssen, S; Ramaswami, G; Davis, EE; Hurd, T; Airik, R; Kasanuki, JM; Van Der Kraak, L; Allen, SJ; Beales, PL; Katsanis, N; Otto, EA; Hildebrandt, F
MLA Citation
Janssen, S, Ramaswami, G, Davis, EE, Hurd, T, Airik, R, Kasanuki, JM, Van Der Kraak, L, Allen, SJ, Beales, PL, Katsanis, N, Otto, EA, and Hildebrandt, F. "Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals." Hum Genet 129.1 (January 2011): 79-90.
PMID
21052717
Source
pubmed
Published In
Human Genetics
Volume
129
Issue
1
Publish Date
2011
Start Page
79
End Page
90
DOI
10.1007/s00439-010-0902-8

Erratum: TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum (Nat. Genet. (2011) 43 (189-196)

Authors
Davis, EE; Zhang, Q; Liu, Q; Diplas, BH; Davey, LM; Hartley, J; Stoetzel, C; Szymanska, K; Ramaswami, G; Logan, CV; Muzny, DM; Young, AC; Wheeler, DA; Cruz, P; Morgan, M; Lewis, LR; Cherukuri, P; Maskeri, B; Hansen, NF; Mullikin, JC; Blakesley, RW; Bouffard, GG; Program, NCS; Gyapay, G; Rieger, S; Tönshoff, B; Kern, I; Soliman, NA; Neuhaus, TJ; Swoboda, KJ; Kayserili, H; Gallagher, TE; Lewis, RA; Bergmann, C; Otto, EA; Saunier, S; Scambler, PJ; Beales, PL; Gleeson, JG; Maher, ER et al.
MLA Citation
Davis, EE, Zhang, Q, Liu, Q, Diplas, BH, Davey, LM, Hartley, J, Stoetzel, C, Szymanska, K, Ramaswami, G, Logan, CV, Muzny, DM, Young, AC, Wheeler, DA, Cruz, P, Morgan, M, Lewis, LR, Cherukuri, P, Maskeri, B, Hansen, NF, Mullikin, JC, Blakesley, RW, Bouffard, GG, Program, NCS, Gyapay, G, Rieger, S, Tönshoff, B, Kern, I, Soliman, NA, Neuhaus, TJ, Swoboda, KJ, Kayserili, H, Gallagher, TE, Lewis, RA, Bergmann, C, Otto, EA, Saunier, S, Scambler, PJ, Beales, PL, Gleeson, JG, and Maher, ER et al. "Erratum: TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum (Nat. Genet. (2011) 43 (189-196)." Nature Genetics 43.5 (2011): 499--.
Source
scival
Published In
Nature Genetics
Volume
43
Issue
5
Publish Date
2011
Start Page
499-
DOI
10.1038/ng0511-499b

Erratum: Disruption of a ciliary B9 protein complex causes meckel syndrome ((The American Journal of Human Genetics (July 2011) 89 (94-110))

Authors
Dowdle, WE; Robinson, JF; Kneist, A; Sirerol-Piquer, MS; Frints, SGM; Corbit, KC; Zaghloul, NA; Lijnschoten, GV; Mulders, L; Verver, DE; Zerres, K; Reed, RR; Attié-Bitach, T; Johnson, CA; García-Verdugo, JM; Katsanis, N; Bergmann, C; Reiter, JF
MLA Citation
Dowdle, WE, Robinson, JF, Kneist, A, Sirerol-Piquer, MS, Frints, SGM, Corbit, KC, Zaghloul, NA, Lijnschoten, GV, Mulders, L, Verver, DE, Zerres, K, Reed, RR, Attié-Bitach, T, Johnson, CA, García-Verdugo, JM, Katsanis, N, Bergmann, C, and Reiter, JF. "Erratum: Disruption of a ciliary B9 protein complex causes meckel syndrome ((The American Journal of Human Genetics (July 2011) 89 (94-110))." American Journal of Human Genetics 89.4 (2011): 589--.
Source
scival
Published In
The American Journal of Human Genetics
Volume
89
Issue
4
Publish Date
2011
Start Page
589-
DOI
10.1016/j.ajhg.2011.09.013

Zebrafish assays of ciliopathies.

In light of the growing list of human disorders associated with their dysfunction, primary cilia have recently come to attention as being important regulators of developmental signaling pathways and downstream processes. These organelles, present on nearly every vertebrate cell type, are highly conserved structures allowing for study across a range of species. Zebrafish, in particular, have emerged as useful organisms in which to explore the consequences of ciliary dysfunction and to model human ciliopathies. Here, we present a range of useful techniques that allow for investigation of various aspects of ciliary function. The described assays capitalize on the hallmark gastrulation defects associated with ciliary defects as well as relative ease of visualization of cilia in whole-mount embryos. Further, we describe our recently developed assay for querying functionality of human gene variants in live developing embryos. Finally, a current catalog of known zebrafish ciliary mutant lines is included. The techniques presented here provide a basic toolkit for in vivo investigation of both the biological and genetic mechanisms underlying a growing class of human diseases.

Authors
Zaghloul, NA; Katsanis, N
MLA Citation
Zaghloul, NA, and Katsanis, N. "Zebrafish assays of ciliopathies." Methods Cell Biol 105 (2011): 257-272.
PMID
21951534
Source
pubmed
Published In
Methods in cell biology
Volume
105
Publish Date
2011
Start Page
257
End Page
272
DOI
10.1016/B978-0-12-381320-6.00011-4

Age-severity relationships in families linked to FCD2 with retroillumination photography.

PURPOSE: Fuchs corneal dystrophy (FCD) is a progressive disorder of the corneal endothelium and is pathologically defined by the presence of guttae, which are excrescences of the Descemet membrane. The present study was undertaken to investigate the age-severity relationship of the FCD2-linked disease phenotype using retroillumination photography and to compare it with the characteristics of FCD1. METHODS: Two large families with multiple affected members were recruited. Exclusion analyses of the known late-onset FCD loci were completed with closely spaced STR markers, whereas genes associated with early- and late-onset FCD were investigated by bidirectional sequencing. Haplotypes were constructed, and two-point LOD scores were calculated. To document age-severity relationships, retroillumination photographs were acquired from members of both families. RESULTS: Parametric linkage and haplotype analysis mapped both families to FCD2 with significant two-point LOD scores. A total of 70,249 guttae were counted in 14 persons from both families. A significant increase in guttae density in the inferotemporal region (P = 0.016) was observed, a pattern similarly observed in a family linked to FCD1. Similarly, FCD2-linked families display an exponential trend in severity with age, as was observed in a family linked to FCD1. Finally, comparison of FCD1 and FCD2 exponential models suggested that the FCD1 phenotype is significantly more severe (P = 0.01). CONCLUSIONS: A combination of genetic mapping and retroillumination photography was used to quantify the severity of the disease phenotype associated with FCD2 and to compare it to the disease characteristics of FCD1. These data suggest that this approach might have sufficient resolution to discriminate between discrete genetic FCD backgrounds, which will potentially aid in patient management.

Authors
McGlumphy, EJ; Yeo, WS; Riazuddin, SA; Al-Saif, A; Wang, J; Eghrari, AO; Meadows, DN; Emmert, DG; Katsanis, N; Gottsch, JD
MLA Citation
McGlumphy, EJ, Yeo, WS, Riazuddin, SA, Al-Saif, A, Wang, J, Eghrari, AO, Meadows, DN, Emmert, DG, Katsanis, N, and Gottsch, JD. "Age-severity relationships in families linked to FCD2 with retroillumination photography." Invest Ophthalmol Vis Sci 51.12 (December 2010): 6298-6302.
PMID
20811064
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
51
Issue
12
Publish Date
2010
Start Page
6298
End Page
6302
DOI
10.1167/iovs.10-5187

Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy.

Homozygous mutations in the Borate Cotransporter SLC4A11 cause two early-onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late-onset Fuchs corneal dystrophy (FCD), a common age-related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late-onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late-onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three-generational family. In silico analyses suggested that most of these substitutions are intolerant, whereas biochemical studies of the mutant protein indicated that these alleles impact the localization and/or posttranslational modification of the protein. These results suggest that heterozygous mutations in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy, PPCD, our data suggest a shared pathomechanism and genetic overlap across several corneal dystrophies.

Authors
Riazuddin, SA; Vithana, EN; Seet, L-F; Liu, Y; Al-Saif, A; Koh, LW; Heng, YM; Aung, T; Meadows, DN; Eghrari, AO; Gottsch, JD; Katsanis, N
MLA Citation
Riazuddin, SA, Vithana, EN, Seet, L-F, Liu, Y, Al-Saif, A, Koh, LW, Heng, YM, Aung, T, Meadows, DN, Eghrari, AO, Gottsch, JD, and Katsanis, N. "Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy." Hum Mutat 31.11 (November 2010): 1261-1268.
PMID
20848555
Source
pubmed
Published In
Human Mutation
Volume
31
Issue
11
Publish Date
2010
Start Page
1261
End Page
1268
DOI
10.1002/humu.21356

A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans.

Authors
Riazuddin, SA; Shahzadi, A; Zeitz, C; Ahmed, ZM; Ayyagari, R; Chavali, VRM; Ponferrada, VG; Audo, I; Michiels, C; Lancelot, M-E; Nasir, IA; Zafar, AU; Khan, SN; Husnain, T; Jiao, X; MacDonald, IM; Riazuddin, S; Sieving, PA; Katsanis, N; Hejtmancik, JF
MLA Citation
Riazuddin, SA, Shahzadi, A, Zeitz, C, Ahmed, ZM, Ayyagari, R, Chavali, VRM, Ponferrada, VG, Audo, I, Michiels, C, Lancelot, M-E, Nasir, IA, Zafar, AU, Khan, SN, Husnain, T, Jiao, X, MacDonald, IM, Riazuddin, S, Sieving, PA, Katsanis, N, and Hejtmancik, JF. "A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness." Am J Hum Genet 87.4 (October 8, 2010): 523-531.
PMID
20850105
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
87
Issue
4
Publish Date
2010
Start Page
523
End Page
531
DOI
10.1016/j.ajhg.2010.08.013

Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

Authors
Otto, EA; Hurd, TW; Airik, R; Chaki, M; Zhou, W; Stoetzel, C; Patil, SB; Levy, S; Ghosh, AK; Murga-Zamalloa, CA; van Reeuwijk, J; Letteboer, SJF; Sang, L; Giles, RH; Liu, Q; Coene, KLM; Estrada-Cuzcano, A; Collin, RWJ; McLaughlin, HM; Held, S; Kasanuki, JM; Ramaswami, G; Conte, J; Lopez, I; Washburn, J; Macdonald, J; Hu, J; Yamashita, Y; Maher, ER; Guay-Woodford, LM; Neumann, HPH; Obermüller, N; Koenekoop, RK; Bergmann, C; Bei, X; Lewis, RA; Katsanis, N; Lopes, V; Williams, DS; Lyons, RH et al.
MLA Citation
Otto, EA, Hurd, TW, Airik, R, Chaki, M, Zhou, W, Stoetzel, C, Patil, SB, Levy, S, Ghosh, AK, Murga-Zamalloa, CA, van Reeuwijk, J, Letteboer, SJF, Sang, L, Giles, RH, Liu, Q, Coene, KLM, Estrada-Cuzcano, A, Collin, RWJ, McLaughlin, HM, Held, S, Kasanuki, JM, Ramaswami, G, Conte, J, Lopez, I, Washburn, J, Macdonald, J, Hu, J, Yamashita, Y, Maher, ER, Guay-Woodford, LM, Neumann, HPH, Obermüller, N, Koenekoop, RK, Bergmann, C, Bei, X, Lewis, RA, Katsanis, N, Lopes, V, Williams, DS, and Lyons, RH et al. "Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy." Nat Genet 42.10 (October 2010): 840-850.
PMID
20835237
Source
pubmed
Published In
Nature Genetics
Volume
42
Issue
10
Publish Date
2010
Start Page
840
End Page
850
DOI
10.1038/ng.662

Planar cell polarity acts through septins to control collective cell movement and ciliogenesis.

The planar cell polarity (PCP) signaling pathway governs collective cell movements during vertebrate embryogenesis, and certain PCP proteins are also implicated in the assembly of cilia. The septins are cytoskeletal proteins controlling behaviors such as cell division and migration. Here, we identified control of septin localization by the PCP protein Fritz as a crucial control point for both collective cell movement and ciliogenesis in Xenopus embryos. We also linked mutations in human Fritz to Bardet-Biedl and Meckel-Gruber syndromes, a notable link given that other genes mutated in these syndromes also influence collective cell movement and ciliogenesis. These findings shed light on the mechanisms by which fundamental cellular machinery, such as the cytoskeleton, is regulated during embryonic development and human disease.

Authors
Kim, SK; Shindo, A; Park, TJ; Oh, EC; Ghosh, S; Gray, RS; Lewis, RA; Johnson, CA; Attie-Bittach, T; Katsanis, N; Wallingford, JB
MLA Citation
Kim, SK, Shindo, A, Park, TJ, Oh, EC, Ghosh, S, Gray, RS, Lewis, RA, Johnson, CA, Attie-Bittach, T, Katsanis, N, and Wallingford, JB. "Planar cell polarity acts through septins to control collective cell movement and ciliogenesis." Science 329.5997 (September 10, 2010): 1337-1340.
PMID
20671153
Source
pubmed
Published In
Science
Volume
329
Issue
5997
Publish Date
2010
Start Page
1337
End Page
1340
DOI
10.1126/science.1191184

Pitchfork regulates primary cilia disassembly and left-right asymmetry.

A variety of developmental disorders have been associated with ciliary defects, yet the controls that govern cilia disassembly are largely unknown. Here we report a mouse embryonic node gene, which we named Pitchfork (Pifo). Pifo associates with ciliary targeting complexes and accumulates at the basal body during cilia disassembly. Haploinsufficiency causes a unique node cilia duplication phenotype, left-right asymmetry defects, and heart failure. This phenotype is likely relevant in humans, because we identified a heterozygous R80K PIFO mutation in a fetus with situs inversus and cystic liver and kidneys, and in patient with double-outflow right ventricle. We show that PIFO, but not R80K PIFO, is sufficient to activate Aurora A, a protooncogenic kinase that induces cilia retraction, and that Pifo/PIFO mutation causes cilia retraction, basal body liberation, and overreplication defects. Thus, the observation of a disassembly phenotype in vivo provides an entry point to understand and categorize ciliary disease. AUTHOR AUDIO:

Authors
Kinzel, D; Boldt, K; Davis, EE; Burtscher, I; Trümbach, D; Diplas, B; Attié-Bitach, T; Wurst, W; Katsanis, N; Ueffing, M; Lickert, H
MLA Citation
Kinzel, D, Boldt, K, Davis, EE, Burtscher, I, Trümbach, D, Diplas, B, Attié-Bitach, T, Wurst, W, Katsanis, N, Ueffing, M, and Lickert, H. "Pitchfork regulates primary cilia disassembly and left-right asymmetry." Dev Cell 19.1 (July 20, 2010): 66-77.
PMID
20643351
Source
pubmed
Published In
Developmental Cell
Volume
19
Issue
1
Publish Date
2010
Start Page
66
End Page
77
DOI
10.1016/j.devcel.2010.06.005

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.

Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.

Authors
Valente, EM; Logan, CV; Mougou-Zerelli, S; Lee, JH; Silhavy, JL; Brancati, F; Iannicelli, M; Travaglini, L; Romani, S; Illi, B; Adams, M; Szymanska, K; Mazzotta, A; Lee, JE; Tolentino, JC; Swistun, D; Salpietro, CD; Fede, C; Gabriel, S; Russ, C; Cibulskis, K; Sougnez, C; Hildebrandt, F; Otto, EA; Held, S; Diplas, BH; Davis, EE; Mikula, M; Strom, CM; Ben-Zeev, B; Lev, D; Sagie, TL; Michelson, M; Yaron, Y; Krause, A; Boltshauser, E; Elkhartoufi, N; Roume, J; Shalev, S; Munnich, A; Saunier, S et al.
MLA Citation
Valente, EM, Logan, CV, Mougou-Zerelli, S, Lee, JH, Silhavy, JL, Brancati, F, Iannicelli, M, Travaglini, L, Romani, S, Illi, B, Adams, M, Szymanska, K, Mazzotta, A, Lee, JE, Tolentino, JC, Swistun, D, Salpietro, CD, Fede, C, Gabriel, S, Russ, C, Cibulskis, K, Sougnez, C, Hildebrandt, F, Otto, EA, Held, S, Diplas, BH, Davis, EE, Mikula, M, Strom, CM, Ben-Zeev, B, Lev, D, Sagie, TL, Michelson, M, Yaron, Y, Krause, A, Boltshauser, E, Elkhartoufi, N, Roume, J, Shalev, S, Munnich, A, and Saunier, S et al. "Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes." Nat Genet 42.7 (July 2010): 619-625.
PMID
20512146
Source
pubmed
Published In
Nature Genetics
Volume
42
Issue
7
Publish Date
2010
Start Page
619
End Page
625
DOI
10.1038/ng.594

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.

Technological advances hold the promise of rapidly catalyzing the discovery of pathogenic variants for genetic disease. However, this possibility is tempered by limitations in interpreting the functional consequences of genetic variation at candidate loci. Here, we present a systematic approach, grounded on physiologically relevant assays, to evaluate the mutational content (125 alleles) of the 14 genes associated with Bardet-Biedl syndrome (BBS). A combination of in vivo assays with subsequent in vitro validation suggests that a significant fraction of BBS-associated mutations have a dominant-negative mode of action. Moreover, we find that a subset of common alleles, previously considered to be benign, are, in fact, detrimental to protein function and can interact with strong rare alleles to modulate disease presentation. These data represent a comprehensive evaluation of genetic load in a multilocus disease. Importantly, superimposition of these results to human genetics data suggests a previously underappreciated complexity in disease architecture that might be shared among diverse clinical phenotypes.

Authors
Zaghloul, NA; Liu, Y; Gerdes, JM; Gascue, C; Oh, EC; Leitch, CC; Bromberg, Y; Binkley, J; Leibel, RL; Sidow, A; Badano, JL; Katsanis, N
MLA Citation
Zaghloul, NA, Liu, Y, Gerdes, JM, Gascue, C, Oh, EC, Leitch, CC, Bromberg, Y, Binkley, J, Leibel, RL, Sidow, A, Badano, JL, and Katsanis, N. "Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome." Proc Natl Acad Sci U S A 107.23 (June 8, 2010): 10602-10607.
PMID
20498079
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
23
Publish Date
2010
Start Page
10602
End Page
10607
DOI
10.1073/pnas.1000219107

Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling.

The expansive family of metazoan ADP-ribosylation factor and ADP-ribosylation factor-like small GTPases is known to play essential roles in modulating membrane trafficking and cytoskeletal functions. Here, we present the crystal structure of ARL6, mutations in which cause Bardet-Biedl syndrome (BBS3), and reveal its unique ring-like localization at the distal end of basal bodies, in proximity to the so-called ciliary gate where vesicles carrying ciliary cargo fuse with the membrane. Overproduction of GDP- or GTP-locked variants of ARL6/BBS3 in vivo influences primary cilium length and abundance. ARL6/BBS3 also modulates Wnt signaling, a signal transduction pathway whose association with cilia in vertebrates is just emerging. Importantly, this signaling function is lost in ARL6 variants containing BBS-associated point mutations. By determining the structure of GTP-bound ARL6/BBS3, coupled with functional assays, we provide a mechanistic explanation for such pathogenic alterations, namely altered nucleotide binding. Our findings therefore establish a previously unknown role for ARL6/BBS3 in mammalian ciliary (dis)assembly and Wnt signaling and provide the first structural information for a BBS protein.

Authors
Wiens, CJ; Tong, Y; Esmail, MA; Oh, E; Gerdes, JM; Wang, J; Tempel, W; Rattner, JB; Katsanis, N; Park, H-W; Leroux, MR
MLA Citation
Wiens, CJ, Tong, Y, Esmail, MA, Oh, E, Gerdes, JM, Wang, J, Tempel, W, Rattner, JB, Katsanis, N, Park, H-W, and Leroux, MR. "Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling." J Biol Chem 285.21 (May 21, 2010): 16218-16230.
PMID
20207729
Source
pubmed
Published In
The Journal of biological chemistry
Volume
285
Issue
21
Publish Date
2010
Start Page
16218
End Page
16230
DOI
10.1074/jbc.M109.070953

A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa.

Tissue-specific alternative splicing is an important mechanism for providing spatiotemporal protein diversity. Here we show that an in-frame splice mutation in BBS8, one of the genes involved in pleiotropic Bardet-Biedl syndrome (BBS), is sufficient to cause nonsyndromic retinitis pigmentosa (RP). A genome-wide scan of a consanguineous RP pedigree mapped the trait to a 5.6 Mb region; subsequent systematic sequencing of candidate transcripts identified a homozygous splice-site mutation in a previously unknown BBS8 exon. The allele segregated with the disorder, was absent from controls, was completely invariant across evolution, and was predicted to lead to the elimination of a 10 amino acid sequence from the protein. Subsequent studies showed the exon to be expressed exclusively in the retina and enriched significantly in the photoreceptor layer. Importantly, we found this exon to represent the major BBS8 mRNA species in the mammalian photoreceptor, suggesting that the encoded 10 amino acids play a pivotal role in the function of BBS8 in this organ. Understanding the role of this additional sequence might therefore inform the mechanism of retinal degeneration in patients with syndromic BBS or other related ciliopathies.

Authors
Riazuddin, SA; Iqbal, M; Wang, Y; Masuda, T; Chen, Y; Bowne, S; Sullivan, LS; Waseem, NH; Bhattacharya, S; Daiger, SP; Zhang, K; Khan, SN; Riazuddin, S; Hejtmancik, JF; Sieving, PA; Zack, DJ; Katsanis, N
MLA Citation
Riazuddin, SA, Iqbal, M, Wang, Y, Masuda, T, Chen, Y, Bowne, S, Sullivan, LS, Waseem, NH, Bhattacharya, S, Daiger, SP, Zhang, K, Khan, SN, Riazuddin, S, Hejtmancik, JF, Sieving, PA, Zack, DJ, and Katsanis, N. "A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa." Am J Hum Genet 86.5 (May 14, 2010): 805-812.
PMID
20451172
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
86
Issue
5
Publish Date
2010
Start Page
805
End Page
812
DOI
10.1016/j.ajhg.2010.04.001

Association of whirlin with Cav1.3 (alpha1D) channels in photoreceptors, defining a novel member of the usher protein network.

PURPOSE: Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome-associated, interacting partners of whirlin and thereby obtain more insights into the function of whirlin. METHODS: The database of ciliary proteins was searched for proteins that are present in both the retina and inner ear and contain a PDZ-binding motif. Interactions with whirlin were evaluated by yeast two-hybrid analyses and validated by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization in the retina with immunofluorescence and immunoelectron microscopy. RESULTS: The L-type calcium channel subunit Ca(v)1.3 (alpha(1D)) specifically interacts with whirlin. In adult photoreceptors, Ca(v)1.3 (alpha(1D)) and whirlin co-localize in the region of the connecting cilium and at the synapse. During murine embryonic development, the expression patterns of the Whrn and Cacna1d genes show significant overlap and include expression in the eye, the inner ear, and the central nervous system. CONCLUSIONS: The findings indicate that Ca(v)1.3 (alpha(1D)) is connected to the Usher protein network. This conclusion leads to the hypothesis that, in the retina, whirlin scaffolds Ca(v)1.3 (alpha(1D)) and therefore contributes to the organization of calcium channels in the photoreceptor cells, where both proteins may be involved in membrane fusions.

Authors
Kersten, FFJ; van Wijk, E; van Reeuwijk, J; van der Zwaag, B; Märker, T; Peters, TA; Katsanis, N; Wolfrum, U; Keunen, JEE; Roepman, R; Kremer, H
MLA Citation
Kersten, FFJ, van Wijk, E, van Reeuwijk, J, van der Zwaag, B, Märker, T, Peters, TA, Katsanis, N, Wolfrum, U, Keunen, JEE, Roepman, R, and Kremer, H. "Association of whirlin with Cav1.3 (alpha1D) channels in photoreceptors, defining a novel member of the usher protein network." Invest Ophthalmol Vis Sci 51.5 (May 2010): 2338-2346.
PMID
19959638
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
51
Issue
5
Publish Date
2010
Start Page
2338
End Page
2346
DOI
10.1167/iovs.09-4650

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Authors
Chen, W; Stambolian, D; Edwards, AO; Branham, KE; Othman, M; Jakobsdottir, J; Tosakulwong, N; Pericak-Vance, MA; Campochiaro, PA; Klein, ML; Tan, PL; Conley, YP; Kanda, A; Kopplin, L; Li, Y; Augustaitis, KJ; Karoukis, AJ; Scott, WK; Agarwal, A; Kovach, JL; Schwartz, SG; Postel, EA; Brooks, M; Baratz, KH; Brown, WL; Complications of Age-Related Macular Degeneration Prevention Trial Research Group, ; Brucker, AJ; Orlin, A; Brown, G; Ho, A; Regillo, C; Donoso, L; Tian, L; Kaderli, B; Hadley, D et al.
MLA Citation
Chen, W, Stambolian, D, Edwards, AO, Branham, KE, Othman, M, Jakobsdottir, J, Tosakulwong, N, Pericak-Vance, MA, Campochiaro, PA, Klein, ML, Tan, PL, Conley, YP, Kanda, A, Kopplin, L, Li, Y, Augustaitis, KJ, Karoukis, AJ, Scott, WK, Agarwal, A, Kovach, JL, Schwartz, SG, Postel, EA, Brooks, M, Baratz, KH, Brown, WL, Complications of Age-Related Macular Degeneration Prevention Trial Research Group, , Brucker, AJ, Orlin, A, Brown, G, Ho, A, Regillo, C, Donoso, L, Tian, L, Kaderli, B, and Hadley, D et al. "Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration." Proc Natl Acad Sci U S A 107.16 (April 20, 2010): 7401-7406.
PMID
20385819
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
16
Publish Date
2010
Start Page
7401
End Page
7406
DOI
10.1073/pnas.0912702107

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.

Authors
Neale, BM; Fagerness, J; Reynolds, R; Sobrin, L; Parker, M; Raychaudhuri, S; Tan, PL; Oh, EC; Merriam, JE; Souied, E; Bernstein, PS; Li, B; Frederick, JM; Zhang, K; Brantley, MA; Lee, AY; Zack, DJ; Campochiaro, B; Campochiaro, P; Ripke, S; Smith, RT; Barile, GR; Katsanis, N; Allikmets, R; Daly, MJ; Seddon, JM
MLA Citation
Neale, BM, Fagerness, J, Reynolds, R, Sobrin, L, Parker, M, Raychaudhuri, S, Tan, PL, Oh, EC, Merriam, JE, Souied, E, Bernstein, PS, Li, B, Frederick, JM, Zhang, K, Brantley, MA, Lee, AY, Zack, DJ, Campochiaro, B, Campochiaro, P, Ripke, S, Smith, RT, Barile, GR, Katsanis, N, Allikmets, R, Daly, MJ, and Seddon, JM. "Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)." Proc Natl Acad Sci U S A 107.16 (April 20, 2010): 7395-7400.
PMID
20385826
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
16
Publish Date
2010
Start Page
7395
End Page
7400
DOI
10.1073/pnas.0912019107

Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping.

BACKGROUND: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterised by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of the time and cost required to screen all 204 coding exons. METHOD: Here, the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci, in BBS individuals from inbred and outbred background, is reported. RESULTS: In a worldwide cohort of 45 families, causative homozygous mutations in 20 families were identified via direct exon sequencing. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). CONCLUSIONS: Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.

Authors
Harville, HM; Held, S; Diaz-Font, A; Davis, EE; Diplas, BH; Lewis, RA; Borochowitz, ZU; Zhou, W; Chaki, M; MacDonald, J; Kayserili, H; Beales, PL; Katsanis, N; Otto, E; Hildebrandt, F
MLA Citation
Harville, HM, Held, S, Diaz-Font, A, Davis, EE, Diplas, BH, Lewis, RA, Borochowitz, ZU, Zhou, W, Chaki, M, MacDonald, J, Kayserili, H, Beales, PL, Katsanis, N, Otto, E, and Hildebrandt, F. "Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping." J Med Genet 47.4 (April 2010): 262-267.
PMID
19797195
Source
pubmed
Published In
Journal of medical genetics
Volume
47
Issue
4
Publish Date
2010
Start Page
262
End Page
267
DOI
10.1136/jmg.2009.071365

Functional modules, mutational load and human genetic disease.

The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals.

Authors
Zaghloul, NA; Katsanis, N
MLA Citation
Zaghloul, NA, and Katsanis, N. "Functional modules, mutational load and human genetic disease." Trends Genet 26.4 (April 2010): 168-176. (Review)
PMID
20226561
Source
pubmed
Published In
Trends in Genetics
Volume
26
Issue
4
Publish Date
2010
Start Page
168
End Page
176
DOI
10.1016/j.tig.2010.01.006

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

Authors
O'Toole, JF; Liu, Y; Davis, EE; Westlake, CJ; Attanasio, M; Otto, EA; Seelow, D; Nurnberg, G; Becker, C; Nuutinen, M; Kärppä, M; Ignatius, J; Uusimaa, J; Pakanen, S; Jaakkola, E; van den Heuvel, LP; Fehrenbach, H; Wiggins, R; Goyal, M; Zhou, W; Wolf, MTF; Wise, E; Helou, J; Allen, SJ; Murga-Zamalloa, CA; Ashraf, S; Chaki, M; Heeringa, S; Chernin, G; Hoskins, BE; Chaib, H; Gleeson, J; Kusakabe, T; Suzuki, T; Isaac, RE; Quarmby, LM; Tennant, B; Fujioka, H; Tuominen, H; Hassinen, I; Lohi, H et al.
MLA Citation
O'Toole, JF, Liu, Y, Davis, EE, Westlake, CJ, Attanasio, M, Otto, EA, Seelow, D, Nurnberg, G, Becker, C, Nuutinen, M, Kärppä, M, Ignatius, J, Uusimaa, J, Pakanen, S, Jaakkola, E, van den Heuvel, LP, Fehrenbach, H, Wiggins, R, Goyal, M, Zhou, W, Wolf, MTF, Wise, E, Helou, J, Allen, SJ, Murga-Zamalloa, CA, Ashraf, S, Chaki, M, Heeringa, S, Chernin, G, Hoskins, BE, Chaib, H, Gleeson, J, Kusakabe, T, Suzuki, T, Isaac, RE, Quarmby, LM, Tennant, B, Fujioka, H, Tuominen, H, Hassinen, I, and Lohi, H et al. "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy." J Clin Invest 120.3 (March 2010): 791-802.
Website
http://hdl.handle.net/10161/4325
PMID
20179356
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
120
Issue
3
Publish Date
2010
Start Page
791
End Page
802
DOI
10.1172/JCI40076

Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Authors
Muller, J; Stoetzel, C; Vincent, MC; Leitch, CC; Laurier, V; Danse, JM; Hellé, S; Marion, V; Bennouna-Greene, V; Vicaire, S; Megarbane, A; Kaplan, J; Drouin-Garraud, V; Hamdani, M; Sigaudy, S; Francannet, C; Roume, J; Bitoun, P; Goldenberg, A; Philip, N; Odent, S; Green, J; Cossée, M; Davis, EE; Katsanis, N; Bonneau, D; Verloes, A; Poch, O; Mandel, JL; Dollfus, H
MLA Citation
Muller, J, Stoetzel, C, Vincent, MC, Leitch, CC, Laurier, V, Danse, JM, Hellé, S, Marion, V, Bennouna-Greene, V, Vicaire, S, Megarbane, A, Kaplan, J, Drouin-Garraud, V, Hamdani, M, Sigaudy, S, Francannet, C, Roume, J, Bitoun, P, Goldenberg, A, Philip, N, Odent, S, Green, J, Cossée, M, Davis, EE, Katsanis, N, Bonneau, D, Verloes, A, Poch, O, Mandel, JL, and Dollfus, H. "Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease." Hum Genet 127.5 (March 2010): 583-593.
PMID
20177705
Source
pubmed
Published In
Human Genetics
Volume
127
Issue
5
Publish Date
2010
Start Page
583
End Page
593
DOI
10.1007/s00439-010-0804-9

Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration.

A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.

Authors
Yang, Z; Tong, Z; Chen, Y; Zeng, J; Lu, F; Sun, X; Zhao, C; Wang, K; Davey, L; Chen, H; London, N; Muramatsu, D; Salasar, F; Carmona, R; Kasuga, D; Wang, X; Bedell, M; Dixie, M; Zhao, P; Yang, R; Gibbs, D; Liu, X; Li, Y; Li, C; Li, Y; Campochiaro, B; Constantine, R; Zack, DJ; Campochiaro, P; Fu, Y; Li, DY; Katsanis, N; Zhang, K
MLA Citation
Yang, Z, Tong, Z, Chen, Y, Zeng, J, Lu, F, Sun, X, Zhao, C, Wang, K, Davey, L, Chen, H, London, N, Muramatsu, D, Salasar, F, Carmona, R, Kasuga, D, Wang, X, Bedell, M, Dixie, M, Zhao, P, Yang, R, Gibbs, D, Liu, X, Li, Y, Li, C, Li, Y, Campochiaro, B, Constantine, R, Zack, DJ, Campochiaro, P, Fu, Y, Li, DY, Katsanis, N, and Zhang, K. "Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. (Published online)" PLoS Genet 6.2 (February 5, 2010): e1000836-.
PMID
20140183
Source
pubmed
Published In
PLoS genetics
Volume
6
Issue
2
Publish Date
2010
Start Page
e1000836
DOI
10.1371/journal.pgen.1000836

Oligogenic disease

© Springer-Verlag Berlin Heidelberg 2010. All rights are reserved.One of the primary goals of human and medical genetics is to assign predictive value to the genotype - that is to say, to use genetic information to assist in the diagnosis and management of disease. Recent work, originating primarily from disorders thought to be traditionally inherited in a Mendelian fashion, have blurred the boundaries between allele causality in monogenic and complex disease. Studies on genetic variation in disease are now revealing that essentially no disorder is transmitted solely in a Mendelian fashion; rather there are always multiple genetic and environmental factors that cause or modulate a disease phenotype. The focus of this chapter, oligogenic disorders, a term describing diseases caused by, or modulated by, a few genes, can provide a conceptual bridge between diseases classically considered monogenic and the poorly understood polygenic or complex disorders. The inheritance of alleles generally follows Mendelian laws of segregation and independent assortment. However, this axiom does not necessarily hold true when the segregation of disease traits is considered. Mendelian inheritance is founded on the notion that a trait (not exclusively a disease phenotype) is transmitted through a single locus; however, even in the most classic monogenic disorders the 1:1 or 3:1 Mendelian ratio of dominant to recessive phenotypes, respectively, cannot explain the breadth of phenotypic variation found in a clinical setting. Although environment also plays a part, new research is showing that a large amount of the pheno-typic variation in Mendelian disorders is due to genetic interaction of several genes (Nat Rev Genet 3:779-789, 2002). In that context, most, if not all, disorders should be considered multifactorial; and the main reason they are Mendelized is that the majority of the phenotype can be attributed to variation/mutations at a single locus.

Authors
Robinson, JF; Katsanis, N
MLA Citation
Robinson, JF, and Katsanis, N. "Oligogenic disease." (January 1, 2010): 243-262. (Chapter)
Source
scopus
Publish Date
2010
Start Page
243
End Page
262
DOI
10.1007/978-3-540-37654-5_8

Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Authors
Riazuddin, SA; Zaghloul, NA; Al-Saif, A; Davey, L; Diplas, BH; Meadows, DN; Eghrari, AO; Minear, MA; Li, Y-J; Klintworth, GK; Afshari, N; Gregory, SG; Gottsch, JD; Katsanis, N
MLA Citation
Riazuddin, SA, Zaghloul, NA, Al-Saif, A, Davey, L, Diplas, BH, Meadows, DN, Eghrari, AO, Minear, MA, Li, Y-J, Klintworth, GK, Afshari, N, Gregory, SG, Gottsch, JD, and Katsanis, N. "Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p." Am J Hum Genet 86.1 (January 2010): 45-53.
PMID
20036349
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
86
Issue
1
Publish Date
2010
Start Page
45
End Page
53
DOI
10.1016/j.ajhg.2009.12.001

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy (Journal of Clinical Investigation (2010) 120, 3 (791-802) DOI: 10.1172/JCI40076)

Authors
O'Toole, JF; Liu, Y; Davis, EE; Westlake, CJ; Attanasio, M; Otto, EA; Seelow, D; Nurnberg, G; Becker, C; Nuutinen, M; Kärppä, M; Ignatius, J; Uusimaa, J; Pakanen, S; Jaakkola, E; Heuvel, LPVD; Fehrenbach, H; Wiggins, R; Zhou, W; Wolf, MTF; Wise, E; Helou, J; Allen, SJ; Murga-Zamalloa, CA; Ashraf, S; Chaki, M; Heeringa, S; Chernin, G; Hoskins, BE; Chaib, H; Gleeson, J; Kusakabe, T; Suzuki, T; Isaac, RE; Quarmby, LM; Tennant, B; Fujioka, H; Tuominen, H; Hassinen, I; Lohi, H; Houten, JLV; Rotig, A et al.
MLA Citation
O'Toole, JF, Liu, Y, Davis, EE, Westlake, CJ, Attanasio, M, Otto, EA, Seelow, D, Nurnberg, G, Becker, C, Nuutinen, M, Kärppä, M, Ignatius, J, Uusimaa, J, Pakanen, S, Jaakkola, E, Heuvel, LPVD, Fehrenbach, H, Wiggins, R, Zhou, W, Wolf, MTF, Wise, E, Helou, J, Allen, SJ, Murga-Zamalloa, CA, Ashraf, S, Chaki, M, Heeringa, S, Chernin, G, Hoskins, BE, Chaib, H, Gleeson, J, Kusakabe, T, Suzuki, T, Isaac, RE, Quarmby, LM, Tennant, B, Fujioka, H, Tuominen, H, Hassinen, I, Lohi, H, Houten, JLV, and Rotig, A et al. "Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy (Journal of Clinical Investigation (2010) 120, 3 (791-802) DOI: 10.1172/JCI40076)." Journal of Clinical Investigation 120.4 (2010): 1362--.
Source
scival
Published In
Journal of Clinical Investigation
Volume
120
Issue
4
Publish Date
2010
Start Page
1362-
DOI
10.1172/JCI40076C1

Progression of Fuchs corneal dystrophy in a family linked to the FCD1 locus.

PURPOSE: Fuchs corneal dystrophy (FCD) is a progressive corneal disease marked by the development of guttae, focal excrescences of Descemet's membrane. Retroillumination photography is a useful technique for illuminating the presence of guttae and has been used to document progression of disease. This study was undertaken to quantitatively assess disease progression in a cohort of individuals with late-onset FCD linked to chromosome 13. METHODS: Retroillumination photography was performed on 13 related individuals (26 eyes) with the FCD1 disease haplotype at a 30- to 34-month interval. Individual guttae were counted in each image and the distribution recorded. A polar coordinate system was used to delineate regional differences in development of guttae. RESULTS: An increase of 29.1% was found in the total number of guttae over approximately 30 months (mean increase of 669 guttae/eye, P < 0.001) among 26 eyes. A rapid rate of progression begins at approximately age 50, representing an exponential increase (r(2) = 0.60) among individuals mildly affected for decades. Individuals with the disease haplotype but with two affected parents demonstrated an earlier disease onset. A significantly greater proportion of guttae were present in the inferotemporal quadrant of the cornea (P < 0.001), an effect that grew in significance over time. CONCLUSIONS: The study demonstrated quantitative progression of FCD with the use of retroillumination photography in an FCD1-linked pedigree. Comparison of severity versus age suggests a rapid increase in the number of guttae at approximately age 50. Individuals with the FCD1 disease haplotype and a second likely genetic lesion exhibit a markedly increased disease severity suggestive of genetic interaction between FCD loci.

Authors
Meadows, DN; Eghrari, AO; Riazuddin, SA; Emmert, DG; Katsanis, N; Gottsch, JD
MLA Citation
Meadows, DN, Eghrari, AO, Riazuddin, SA, Emmert, DG, Katsanis, N, and Gottsch, JD. "Progression of Fuchs corneal dystrophy in a family linked to the FCD1 locus." Invest Ophthalmol Vis Sci 50.12 (December 2009): 5662-5666.
PMID
19608546
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
50
Issue
12
Publish Date
2009
Start Page
5662
End Page
5666
DOI
10.1167/iovs.09-3568

Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1-q35.2.

PURPOSE: To identify the disease locus associated with autosomal dominant Fuchs corneal dystrophy (FCD) in a large family and to compare the progression of severity in families mapped to the FCD1 and FCD2 loci. METHODS: Seventeen individuals in a large family were examined by slit lamp biomicroscopy. Blood samples were collected, DNA was extracted, and a genome-wide scan was performed with a microarray SNP chip. After initial generation of a genome-wide, two-point LOD score, linkage was confirmed and the critical interval was established by genotyping of short tandem repeat (STR) microsatellite markers. RESULTS: A genome-wide linkage scan localized the disease interval to the long arm of chromosome 5, with a maximum two-point parametric LOD score of 3.41. Haplotype analyses refined the critical interval to 5q33.1-q35.2, spanning a 27-Mb (29-cM) region. Clinical examination of affected individuals in this family revealed an early onset of FCD at approximately age 40, after which progression of the disease was significantly attenuated compared to the FCD1- and FCD2-linked families. CONCLUSIONS: Late-onset FCD is linked to a novel locus on 5q33.1-q35.2 and is associated with a milder severity in age at onset and rate of progression than the FCD1 and FCD2 loci. Correlation of individual genotypes with unique rates of disease progression will provide important tools for disease management, as well as for identifying the underlying genetic lesion, offer insight into the pathomechanism of FCD.

Authors
Riazuddin, SA; Eghrari, AO; Al-Saif, A; Davey, L; Meadows, DN; Katsanis, N; Gottsch, JD
MLA Citation
Riazuddin, SA, Eghrari, AO, Al-Saif, A, Davey, L, Meadows, DN, Katsanis, N, and Gottsch, JD. "Linkage of a mild late-onset phenotype of Fuchs corneal dystrophy to a novel locus at 5q33.1-q35.2." Invest Ophthalmol Vis Sci 50.12 (December 2009): 5667-5671.
PMID
19608540
Source
pubmed
Published In
Investigative Ophthalmology and Visual Science
Volume
50
Issue
12
Publish Date
2009
Start Page
5667
End Page
5671
DOI
10.1167/iovs.09-3764

Thermosensory and mechanosensory perception in human genetic disease.

Peripheral sensory perception is established through an elaborate network of specialized neurons that mediate the translation of extraorganismal stimuli through the use of a broad array of receptors and downstream effector molecules. Studies of human genetic disorders, as well as mouse and other animal models, have identified some of the key molecules necessary for peripheral innervation and function. These findings have, in turn, yielded new insights into the developmental networks and homeostatic mechanisms necessary for the transformation of external stimuli into interpretable electrical impulses. In this review, we will summarize and discuss some of the genes/proteins implicated in two particular aspects of sensory perception, thermosensation and mechanosensation, highlighting pathways whose perturbation leads to both isolated and syndromic sensory deficits.

Authors
Tan, PL; Katsanis, N
MLA Citation
Tan, PL, and Katsanis, N. "Thermosensory and mechanosensory perception in human genetic disease." Hum Mol Genet 18.R2 (October 15, 2009): R146-R155. (Review)
PMID
19808790
Source
pubmed
Published In
Human Molecular Genetics
Volume
18
Issue
R2
Publish Date
2009
Start Page
R146
End Page
R155
DOI
10.1093/hmg/ddp412

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.

Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.

Authors
de Pontual, L; Zaghloul, NA; Thomas, S; Davis, EE; McGaughey, DM; Dollfus, H; Baumann, C; Bessling, SL; Babarit, C; Pelet, A; Gascue, C; Beales, P; Munnich, A; Lyonnet, S; Etchevers, H; Attie-Bitach, T; Badano, JL; McCallion, AS; Katsanis, N; Amiel, J
MLA Citation
de Pontual, L, Zaghloul, NA, Thomas, S, Davis, EE, McGaughey, DM, Dollfus, H, Baumann, C, Bessling, SL, Babarit, C, Pelet, A, Gascue, C, Beales, P, Munnich, A, Lyonnet, S, Etchevers, H, Attie-Bitach, T, Badano, JL, McCallion, AS, Katsanis, N, and Amiel, J. "Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease." Proc Natl Acad Sci U S A 106.33 (August 18, 2009): 13921-13926.
PMID
19666486
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
33
Publish Date
2009
Start Page
13921
End Page
13926
DOI
10.1073/pnas.0901219106

A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.

Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.

Authors
Khanna, H; Davis, EE; Murga-Zamalloa, CA; Estrada-Cuzcano, A; Lopez, I; den Hollander, AI; Zonneveld, MN; Othman, MI; Waseem, N; Chakarova, CF; Maubaret, C; Diaz-Font, A; MacDonald, I; Muzny, DM; Wheeler, DA; Morgan, M; Lewis, LR; Logan, CV; Tan, PL; Beer, MA; Inglehearn, CF; Lewis, RA; Jacobson, SG; Bergmann, C; Beales, PL; Attié-Bitach, T; Johnson, CA; Otto, EA; Bhattacharya, SS; Hildebrandt, F; Gibbs, RA; Koenekoop, RK; Swaroop, A; Katsanis, N
MLA Citation
Khanna, H, Davis, EE, Murga-Zamalloa, CA, Estrada-Cuzcano, A, Lopez, I, den Hollander, AI, Zonneveld, MN, Othman, MI, Waseem, N, Chakarova, CF, Maubaret, C, Diaz-Font, A, MacDonald, I, Muzny, DM, Wheeler, DA, Morgan, M, Lewis, LR, Logan, CV, Tan, PL, Beer, MA, Inglehearn, CF, Lewis, RA, Jacobson, SG, Bergmann, C, Beales, PL, Attié-Bitach, T, Johnson, CA, Otto, EA, Bhattacharya, SS, Hildebrandt, F, Gibbs, RA, Koenekoop, RK, Swaroop, A, and Katsanis, N. "A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies." Nat Genet 41.6 (June 2009): 739-745.
PMID
19430481
Source
pubmed
Published In
Nature Genetics
Volume
41
Issue
6
Publish Date
2009
Start Page
739
End Page
745
DOI
10.1038/ng.366

The vertebrate primary cilium in development, homeostasis, and disease.

Cilia are complex structures that have garnered interest because of their roles in vertebrate development and their involvement in human genetic disorders. In contrast to multicellular invertebrates in which cilia are restricted to specific cell types, these organelles are found almost ubiquitously in vertebrate cells, where they serve a diverse set of signaling functions. Here, we highlight properties of vertebrate cilia, with particular emphasis on their relationship with other subcellular structures, and explore the physiological consequences of ciliary dysfunction.

Authors
Gerdes, JM; Davis, EE; Katsanis, N
MLA Citation
Gerdes, JM, Davis, EE, and Katsanis, N. "The vertebrate primary cilium in development, homeostasis, and disease." Cell 137.1 (April 3, 2009): 32-45. (Review)
PMID
19345185
Source
pubmed
Published In
Cell
Volume
137
Issue
1
Publish Date
2009
Start Page
32
End Page
45
DOI
10.1016/j.cell.2009.03.023

Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins.

Meckel syndrome (MKS) is a ciliopathy characterized by encephalocele, cystic renal disease, liver fibrosis and polydactyly. An identifying feature of MKS1, one of six MKS-associated proteins, is the presence of a B9 domain of unknown function. Using phylogenetic analyses, we show that this domain occurs exclusively within a family of three proteins distributed widely in ciliated organisms. Consistent with a ciliary role, all Caenorhabditis elegans B9-domain-containing proteins, MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia. Their subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins. This localization is evolutionarily conserved, because the human orthologues also localize to basal bodies, as well as cilia. As reported for MKS1, disrupting human MKSR1 or MKSR2 causes ciliogenesis defects. By contrast, single, double and triple C. elegans mks/mksr mutants do not display overt defects in ciliary structure, intraflagellar transport or chemosensation. However, we find genetic interactions between all double mks/mksr mutant combinations, manifesting as an increased lifespan phenotype, which is due to abnormal insulin-IGF-I signaling. Our findings therefore demonstrate functional interactions between a novel family of proteins associated with basal bodies or cilia, providing new insights into the molecular etiology of a pleiotropic human disorder.

Authors
Bialas, NJ; Inglis, PN; Li, C; Robinson, JF; Parker, JDK; Healey, MP; Davis, EE; Inglis, CD; Toivonen, T; Cottell, DC; Blacque, OE; Quarmby, LM; Katsanis, N; Leroux, MR
MLA Citation
Bialas, NJ, Inglis, PN, Li, C, Robinson, JF, Parker, JDK, Healey, MP, Davis, EE, Inglis, CD, Toivonen, T, Cottell, DC, Blacque, OE, Quarmby, LM, Katsanis, N, and Leroux, MR. "Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins." J Cell Sci 122.Pt 5 (March 1, 2009): 611-624.
PMID
19208769
Source
pubmed
Published In
Journal of cell science
Volume
122
Issue
Pt 5
Publish Date
2009
Start Page
611
End Page
624
DOI
10.1242/jcs.028621

Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy.

Bardet-Biedl syndrome (BBS) is a multisystemic disorder typified by developmental and progressive degenerative defects. A combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology, which has in turn contributed to the improved understanding of the functions of the primary cilium in humans and other vertebrates. Here we discuss the evidence linking the clinical BBS phenotype to ciliary defects, highlight how the genetic and cellular characteristics of BBS overlap with and inform other ciliary disorders, and explore the possible mechanistic underpinnings of ciliary dysfunction.

Authors
Zaghloul, NA; Katsanis, N
MLA Citation
Zaghloul, NA, and Katsanis, N. "Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy." J Clin Invest 119.3 (March 2009): 428-437. (Review)
PMID
19252258
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
119
Issue
3
Publish Date
2009
Start Page
428
End Page
437
DOI
10.1172/JCI37041

From association to causality: the new frontier for complex traits.

Technological and analytical advances have led to an unprecedented catalog of genomic regions associated with a broad range of clinically relevant phenotypes in humans. However, some examples notwithstanding, the causes of the overwhelming majority of genetic diseases remain obscure. More importantly, an emerging lesson from genome-wide association studies is that, in most instances, the resolution necessary for identifying actual genes that underlie the phenotype is limited, as is our ability to develop mechanistic, testable disease models from such studies. These new realities will probably necessitate a paradigm shift in our approach to complex traits, for which the combinatorial application of genomic and functional studies will be necessary to understand the mechanism and pathology of genetic disease. Here I will discuss these issues and highlight how additional sequencing and genotyping of ever-increasing cohort sizes without functional interpretation is unlikely to improve our ability to dissect the genetic basis of complex traits.

Authors
Katsanis, N
MLA Citation
Katsanis, N. "From association to causality: the new frontier for complex traits. (Published online)" Genome Med 1.2 (February 25, 2009): 23-.
PMID
19341494
Source
pubmed
Published In
Genome Medicine: medicine in the post-genomic era
Volume
1
Issue
2
Publish Date
2009
Start Page
23
DOI
10.1186/gm23

The authors reply

Authors
Ambati, J; Katsanis, N; Zhang, K
MLA Citation
Ambati, J, Katsanis, N, and Zhang, K. "The authors reply." New England Journal of Medicine 360.21 (2009): 2255-2256.
Source
scival
Published In
The New England journal of medicine
Volume
360
Issue
21
Publish Date
2009
Start Page
2255
End Page
2256

Analysis of 30 genes (355 SNPS) related to energy homeostasis for association with adiposity in European-American and Yup'ik Eskimo populations.

OBJECTIVE: Human adiposity is highly heritable, but few of the genes that predispose to obesity in most humans are known. We tested candidate genes in pathways related to food intake and energy expenditure for association with measures of adiposity. METHODS: We studied 355 genetic variants in 30 candidate genes in 7 molecular pathways related to obesity in two groups of adult subjects: 1,982 unrelated European Americans living in the New York metropolitan area drawn from the extremes of their body mass index (BMI) distribution and 593 related Yup'ik Eskimos living in rural Alaska characterized for BMI, body composition, waist circumference, and skin fold thicknesses. Data were analyzed by using a mixed model in conjunction with a false discovery rate (FDR) procedure to correct for multiple testing. RESULTS: After correcting for multiple testing, two single nucleotide polymorphisms (SNPs) in Ghrelin (GHRL) (rs35682 and rs35683) were associated with BMI in the New York European Americans. This association was not replicated in the Yup'ik participants. There was no evidence for gene x gene interactions among genes within the same molecular pathway after adjusting for multiple testing via FDR control procedure. CONCLUSION: Genetic variation in GHRL may have a modest impact on BMI in European Americans.

Authors
Chung, WK; Patki, A; Matsuoka, N; Boyer, BB; Liu, N; Musani, SK; Goropashnaya, AV; Tan, PL; Katsanis, N; Johnson, SB; Gregersen, PK; Allison, DB; Leibel, RL; Tiwari, HK
MLA Citation
Chung, WK, Patki, A, Matsuoka, N, Boyer, BB, Liu, N, Musani, SK, Goropashnaya, AV, Tan, PL, Katsanis, N, Johnson, SB, Gregersen, PK, Allison, DB, Leibel, RL, and Tiwari, HK. "Analysis of 30 genes (355 SNPS) related to energy homeostasis for association with adiposity in European-American and Yup'ik Eskimo populations." Hum Hered 67.3 (2009): 193-205.
PMID
19077438
Source
pubmed
Published In
Human heredity
Volume
67
Issue
3
Publish Date
2009
Start Page
193
End Page
205
DOI
10.1159/000181158

CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.

Authors
Gorden, NT; Arts, HH; Parisi, MA; Coene, KLM; Letteboer, SJF; van Beersum, SEC; Mans, DA; Hikida, A; Eckert, M; Knutzen, D; Alswaid, AF; Ozyurek, H; Dibooglu, S; Otto, EA; Liu, Y; Davis, EE; Hutter, CM; Bammler, TK; Farin, FM; Dorschner, M; Topçu, M; Zackai, EH; Rosenthal, P; Owens, KN; Katsanis, N; Vincent, JB; Hildebrandt, F; Rubel, EW; Raible, DW; Knoers, NVAM; Chance, PF; Roepman, R; Moens, CB; Glass, IA; Doherty, D
MLA Citation
Gorden, NT, Arts, HH, Parisi, MA, Coene, KLM, Letteboer, SJF, van Beersum, SEC, Mans, DA, Hikida, A, Eckert, M, Knutzen, D, Alswaid, AF, Ozyurek, H, Dibooglu, S, Otto, EA, Liu, Y, Davis, EE, Hutter, CM, Bammler, TK, Farin, FM, Dorschner, M, Topçu, M, Zackai, EH, Rosenthal, P, Owens, KN, Katsanis, N, Vincent, JB, Hildebrandt, F, Rubel, EW, Raible, DW, Knoers, NVAM, Chance, PF, Roepman, R, Moens, CB, Glass, IA, and Doherty, D. "CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290." Am J Hum Genet 83.5 (November 2008): 559-571.
PMID
18950740
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
83
Issue
5
Publish Date
2008
Start Page
559
End Page
571
DOI
10.1016/j.ajhg.2008.10.002

Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

Authors
Yang, Z; Stratton, C; Francis, PJ; Kleinman, ME; Tan, PL; Gibbs, D; Tong, Z; Chen, H; Constantine, R; Yang, X; Chen, Y; Zeng, J; Davey, L; Ma, X; Hau, VS; Wang, C; Harmon, J; Buehler, J; Pearson, E; Patel, S; Kaminoh, Y; Watkins, S; Luo, L; Zabriskie, NA; Bernstein, PS; Cho, W; Schwager, A; Hinton, DR; Klein, ML; Hamon, SC; Simmons, E; Yu, B; Campochiaro, B; Sunness, JS; Campochiaro, P; Jorde, L; Parmigiani, G; Zack, DJ; Katsanis, N; Ambati, J; Zhang, K
MLA Citation
Yang, Z, Stratton, C, Francis, PJ, Kleinman, ME, Tan, PL, Gibbs, D, Tong, Z, Chen, H, Constantine, R, Yang, X, Chen, Y, Zeng, J, Davey, L, Ma, X, Hau, VS, Wang, C, Harmon, J, Buehler, J, Pearson, E, Patel, S, Kaminoh, Y, Watkins, S, Luo, L, Zabriskie, NA, Bernstein, PS, Cho, W, Schwager, A, Hinton, DR, Klein, ML, Hamon, SC, Simmons, E, Yu, B, Campochiaro, B, Sunness, JS, Campochiaro, P, Jorde, L, Parmigiani, G, Zack, DJ, Katsanis, N, Ambati, J, and Zhang, K. "Toll-like receptor 3 and geographic atrophy in age-related macular degeneration." N Engl J Med 359.14 (October 2, 2008): 1456-1463.
PMID
18753640
Source
pubmed
Published In
The New England journal of medicine
Volume
359
Issue
14
Publish Date
2008
Start Page
1456
End Page
1463
DOI
10.1056/NEJMoa0802437

Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses.

CONTEXT: A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ). OBJECTIVES: To show that pericentriolar material 1 protein (PCM1) forms a complex at the centrosome with disrupted-in-schizophrenia 1 (DISC1) and Bardet-Biedl syndrome 4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in an SZ population. DESIGN: Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and coimmunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNA interference. The PCM1 gene was examined by sequencing 39 exons and flanking splice sites. SETTING: Probands and controls were from the collection of one of us (A.E.P.). PATIENTS: Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22 and 219 white controls. MAIN OUTCOME MEASURES: Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; and variant discovery in PCM1 in patients with SZ. RESULTS: PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4 and are exacerbated by the concomitant suppression of both. Furthermore, a nonsense mutation that segregates with SZ spectrum psychosis was found in 1 family. CONCLUSIONS: Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases, including SZ.

Authors
Kamiya, A; Tan, PL; Kubo, K-I; Engelhard, C; Ishizuka, K; Kubo, A; Tsukita, S; Pulver, AE; Nakajima, K; Cascella, NG; Katsanis, N; Sawa, A
MLA Citation
Kamiya, A, Tan, PL, Kubo, K-I, Engelhard, C, Ishizuka, K, Kubo, A, Tsukita, S, Pulver, AE, Nakajima, K, Cascella, NG, Katsanis, N, and Sawa, A. "Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses." Arch Gen Psychiatry 65.9 (September 2008): 996-1006.
PMID
18762586
Source
pubmed
Published In
Archives of General Psychiatry
Volume
65
Issue
9
Publish Date
2008
Start Page
996
End Page
1006
DOI
10.1001/archpsyc.65.9.996

Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.

Meckel-Gruber syndrome (MKS) is a genetically heterogeneous, neonatally lethal malformation and the most common form of syndromic neural tube defect (NTD). To date, several MKS-associated genes have been identified whose protein products affect ciliary function. Here we show that mutations in MKS1, MKS3 and CEP290 (also known as NPHP6) either can cause Bardet-Biedl syndrome (BBS) or may have a potential epistatic effect on mutations in known BBS-associated loci. Five of six families with both MKS1 and BBS mutations manifested seizures, a feature that is not a typical component of either syndrome. Functional studies in zebrafish showed that mks1 is necessary for gastrulation movements and that it interacts genetically with known bbs genes. Similarly, we found two families with missense or splice mutations in MKS3, in one of which the affected individual also bears a homozygous nonsense mutation in CEP290 that is likely to truncate the C terminus of the protein. These data extend the genetic stratification of ciliopathies and suggest that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum.

Authors
Leitch, CC; Zaghloul, NA; Davis, EE; Stoetzel, C; Diaz-Font, A; Rix, S; Alfadhel, M; Lewis, RA; Eyaid, W; Banin, E; Dollfus, H; Beales, PL; Badano, JL; Katsanis, N
MLA Citation
Leitch, CC, Zaghloul, NA, Davis, EE, Stoetzel, C, Diaz-Font, A, Rix, S, Alfadhel, M, Lewis, RA, Eyaid, W, Banin, E, Dollfus, H, Beales, PL, Badano, JL, and Katsanis, N. "Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome." Nat Genet 40.4 (April 2008): 443-448.
PMID
18327255
Source
pubmed
Published In
Nature Genetics
Volume
40
Issue
4
Publish Date
2008
Start Page
443
End Page
448
DOI
10.1038/ng.97

An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes.

MIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 (Disrupted-in-Schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development.

Authors
Li, C; Inglis, PN; Leitch, CC; Efimenko, E; Zaghloul, NA; Mok, CA; Davis, EE; Bialas, NJ; Healey, MP; Héon, E; Zhen, M; Swoboda, P; Katsanis, N; Leroux, MR
MLA Citation
Li, C, Inglis, PN, Leitch, CC, Efimenko, E, Zaghloul, NA, Mok, CA, Davis, EE, Bialas, NJ, Healey, MP, Héon, E, Zhen, M, Swoboda, P, Katsanis, N, and Leroux, MR. "An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes. (Published online)" PLoS Genet 4.3 (March 28, 2008): e1000044-.
PMID
18369462
Source
pubmed
Published In
PLoS genetics
Volume
4
Issue
3
Publish Date
2008
Start Page
e1000044
DOI
10.1371/journal.pgen.1000044

Corrigendum: Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome (Nature Genetics (2008) 40, (443-448))

Authors
Leitch, CC; Zaghloul, NA; Davis, EE; Stoetzel, C; Diaz-Font, A; Rix, S; Al-Fadhel, M; Lewis, RA; Eyaid, W; Banin, E; Dollfus, H; Beales, PL; Badano, JL; Katsanis, N
MLA Citation
Leitch, CC, Zaghloul, NA, Davis, EE, Stoetzel, C, Diaz-Font, A, Rix, S, Al-Fadhel, M, Lewis, RA, Eyaid, W, Banin, E, Dollfus, H, Beales, PL, Badano, JL, and Katsanis, N. "Corrigendum: Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome (Nature Genetics (2008) 40, (443-448))." Nature Genetics 40.7 (2008): 927--.
Source
scival
Published In
Nature Genetics
Volume
40
Issue
7
Publish Date
2008
Start Page
927-
DOI
10.1038/ng0708-927b

Ciliary function and Wnt signal modulation.

With the increase in complexity of morphogenetic signaling cascades over the course of evolution and the emergence of broadly ciliated organisms, the cilium seems to have acquired a role as regulator of paracrine signal transduction. Recently, several lines of evidence have provided a link between basal body and ciliary proteins and Wnt signaling. In this chapter, we will evaluate the evidence linking the basal body and cilium with the regulation of beta-catenin-dependent (canonical) and beta-catenin-independent (noncanonical) signaling processes as well as which role(s) Wnt signaling might play in ciliogenesis. In addition, we will discuss aberrant Wnt signaling could contribute to phenotypes common to most ciliopathies and why these phenotypes might be driven by loss of noncanonical rather than gain of noncanonical Wnt signaling.

Authors
Gerdes, JM; Katsanis, N
MLA Citation
Gerdes, JM, and Katsanis, N. "Ciliary function and Wnt signal modulation." Curr Top Dev Biol 85 (2008): 175-195. (Review)
PMID
19147006
Source
pubmed
Published In
Current topics in developmental biology
Volume
85
Publish Date
2008
Start Page
175
End Page
195
DOI
10.1016/S0070-2153(08)00807-7

Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an oligogenic syndrome whose manifestations include retinal degeneration, renal abnormalities, obesity and polydactylia. Evidence suggests that the main etiopathophysiology of this syndrome is impaired intraflagellar transport (IFT). In this study, we study the Bbs4-null mouse and investigate photoreceptor structure and function after loss of this gene. We find that Bbs4-null mice have defects in the transport of phototransduction proteins from the inner segments to the outer segments, before signs of cell death. Additionally, we show defects in synaptic transmission from the photoreceptors to secondary neurons of the visual system, demonstrating multiple functions for BBS4 in photoreceptors.

Authors
Abd-El-Barr, MM; Sykoudis, K; Andrabi, S; Eichers, ER; Pennesi, ME; Tan, PL; Wilson, JH; Katsanis, N; Lupski, JR; Wu, SM
MLA Citation
Abd-El-Barr, MM, Sykoudis, K, Andrabi, S, Eichers, ER, Pennesi, ME, Tan, PL, Wilson, JH, Katsanis, N, Lupski, JR, and Wu, SM. "Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet-Biedl syndrome." Vision Res 47.27 (December 2007): 3394-3407.
PMID
18022666
Source
pubmed
Published In
Vision Research
Volume
47
Issue
27
Publish Date
2007
Start Page
3394
End Page
3407
DOI
10.1016/j.visres.2007.09.016

Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response.

Primary cilia and basal bodies are evolutionarily conserved organelles that mediate communication between the intracellular and extracellular environments. Here we show that bbs1, bbs4 and mkks (also known as bbs6), which encode basal body proteins, are required for convergence and extension in zebrafish and interact with wnt11 and wnt5b. Suppression of bbs1, bbs4 and mkks transcripts results in stabilization of beta-catenin with concomitant upregulation of T-cell factor (TCF)-dependent transcription in both zebrafish embryos and mammalian ciliated cells, a defect phenocopied by the silencing of the axonemal kinesin subunit KIF3A but not by chemical disruption of the cytoplasmic microtubule network. These observations are attributable partly to defective degradation by the proteasome; suppression of BBS4 leads to perturbed proteasomal targeting and concomitant accumulation of cytoplasmic beta-catenin. Cumulatively, our data indicate that the basal body is an important regulator of Wnt signal interpretation through selective proteolysis and suggest that defects in this system may contribute to phenotypes pathognomonic of human ciliopathies.

Authors
Gerdes, JM; Liu, Y; Zaghloul, NA; Leitch, CC; Lawson, SS; Kato, M; Beachy, PA; Beales, PL; DeMartino, GN; Fisher, S; Badano, JL; Katsanis, N
MLA Citation
Gerdes, JM, Liu, Y, Zaghloul, NA, Leitch, CC, Lawson, SS, Kato, M, Beachy, PA, Beales, PL, DeMartino, GN, Fisher, S, Badano, JL, and Katsanis, N. "Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response." Nat Genet 39.11 (November 2007): 1350-1360.
PMID
17906624
Source
pubmed
Published In
Nature Genetics
Volume
39
Issue
11
Publish Date
2007
Start Page
1350
End Page
1360
DOI
10.1038/ng.2007.12

Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function.

Reception and interpretation of environmental stimuli is critical for the survival of all organisms. Here, we show that the ablation of BBS1 and BBS4, two genes mutated in Bardet-Biedl syndrome and that encode proteins that localize near the centrioles of sensory neurons, leads to alterations of s.c. sensory innervation and trafficking of the thermosensory channel TRPV1 and the mechanosensory channel STOML3, with concomitant defects in peripheral thermosensation and mechanosensation. The thermosensory phenotype is recapitulated in Caenorhabditis elegans, because BBS mutants manifest deficient thermosensory responses at both physiological and nociceptive temperatures and defective trafficking of OSM-9, a polymodal sensory channel protein and a functional homolog of TRPV1 or TRPV4. Our findings suggest a hitherto unrecognized, but essential, role for mammalian basal body proteins in the acquisition of mechano- and thermosensory stimuli and highlight potentially clinical features of ciliopathies in humans.

Authors
Tan, PL; Barr, T; Inglis, PN; Mitsuma, N; Huang, SM; Garcia-Gonzalez, MA; Bradley, BA; Coforio, S; Albrecht, PJ; Watnick, T; Germino, GG; Beales, PL; Caterina, MJ; Leroux, MR; Rice, FL; Katsanis, N
MLA Citation
Tan, PL, Barr, T, Inglis, PN, Mitsuma, N, Huang, SM, Garcia-Gonzalez, MA, Bradley, BA, Coforio, S, Albrecht, PJ, Watnick, T, Germino, GG, Beales, PL, Caterina, MJ, Leroux, MR, Rice, FL, and Katsanis, N. "Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function." Proc Natl Acad Sci U S A 104.44 (October 30, 2007): 17524-17529.
PMID
17959775
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
104
Issue
44
Publish Date
2007
Start Page
17524
End Page
17529
DOI
10.1073/pnas.0706618104

Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease.

Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.

Authors
de Pontual, L; Pelet, A; Clement-Ziza, M; Trochet, D; Antonarakis, SE; Attie-Bitach, T; Beales, PL; Blouin, J-L; Dastot-Le Moal, F; Dollfus, H; Goossens, M; Katsanis, N; Touraine, R; Feingold, J; Munnich, A; Lyonnet, S; Amiel, J
MLA Citation
de Pontual, L, Pelet, A, Clement-Ziza, M, Trochet, D, Antonarakis, SE, Attie-Bitach, T, Beales, PL, Blouin, J-L, Dastot-Le Moal, F, Dollfus, H, Goossens, M, Katsanis, N, Touraine, R, Feingold, J, Munnich, A, Lyonnet, S, and Amiel, J. "Epistatic interactions with a common hypomorphic RET allele in syndromic Hirschsprung disease." Hum Mutat 28.8 (August 2007): 790-796.
PMID
17397038
Source
pubmed
Published In
Human Mutation
Volume
28
Issue
8
Publish Date
2007
Start Page
790
End Page
796
DOI
10.1002/humu.20517

Cell polarization defects in early heart development.

Authors
Davis, EE; Katsanis, N
MLA Citation
Davis, EE, and Katsanis, N. "Cell polarization defects in early heart development." Circ Res 101.2 (July 20, 2007): 122-124.
PMID
17641235
Source
pubmed
Published In
Circulation Research
Volume
101
Issue
2
Publish Date
2007
Start Page
122
End Page
124
DOI
10.1161/CIRCRESAHA.107.157446

Population bottlenecks as a potential major shaping force of human genome architecture.

The modern synthetic view of human evolution proposes that the fixation of novel mutations is driven by the balance among selective advantage, selective disadvantage, and genetic drift. When considering the global architecture of the human genome, the same model can be applied to understanding the rapid acquisition and proliferation of exogenous DNA. To explore the evolutionary forces that might have morphed human genome architecture, we investigated the origin, composition, and functional potential of numts (nuclear mitochondrial pseudogenes), partial copies of the mitochondrial genome found abundantly in chromosomal DNA. Our data indicate that these elements are unlikely to be advantageous, since they possess no gross positional, transcriptional, or translational features that might indicate beneficial functionality subsequent to integration. Using sequence analysis and fossil dating, we also show a probable burst of integration of numts in the primate lineage that centers on the prosimian-anthropoid split, mimics closely the temporal distribution of Alu and processed pseudogene acquisition, and coincides with the major climatic change at the Paleocene-Eocene boundary. We therefore propose a model according to which the gross architecture and repeat distribution of the human genome can be largely accounted for by a population bottleneck early in the anthropoid lineage and subsequent effectively neutral fixation of repetitive DNA, rather than positive selection or unusual insertion pressures.

Authors
Gherman, A; Chen, PE; Teslovich, TM; Stankiewicz, P; Withers, M; Kashuk, CS; Chakravarti, A; Lupski, JR; Cutler, DJ; Katsanis, N
MLA Citation
Gherman, A, Chen, PE, Teslovich, TM, Stankiewicz, P, Withers, M, Kashuk, CS, Chakravarti, A, Lupski, JR, Cutler, DJ, and Katsanis, N. "Population bottlenecks as a potential major shaping force of human genome architecture." PLoS Genet 3.7 (July 2007): e119-.
PMID
17658953
Source
pubmed
Published In
PLoS genetics
Volume
3
Issue
7
Publish Date
2007
Start Page
e119
DOI
10.1371/journal.pgen.0030119

Bardet-Biedl Syndrome in an African-American patient: should the diagnostic criteria be expanded to include hydrometrocolpos?

Bardet-Biedl Syndrome (BBS) is a multisystemic disorder diagnosed on the basis of a combination of primary and secondary clinical features that include retinal dystrophy, obesity, polydactyly, cognitive dysfunction, and renal malformations. We report a unique case of BBS in a 13-year old girl of African-American descent who presented with retinitis pigmentosa, obesity, polydactyly, learning disabilities, precocious puberty, hypertension, renal cysts, and Hirschprung disease. Further evaluation revealed a history of precocious puberty, which is antithetical to the common manifestations of BBS, while neuroimaging was suggestive of periventricular leukomalacia and neuro-electrophysiologic studies revealed diffuse cerebral disturbance, which may contribute to her neurological abnormalities. The patient was also diagnosed with hydrometrocolpos, a finding typical of McKusick-Kaufman Syndrome (MKKS) but infrequent in other disorders. This observation, together with recent findings in some mouse models of BBS, raises the question of whether hydrometrocolpos should be considered as an additional diagnostic criterion for BBS to be used in females in parallel to the criterion of hypogonadism in males, thereby improving diagnostic sensitivity.

Authors
Toma, HS; Tan, PL; McKusick, VA; Katsanis, N; Adams, NA
MLA Citation
Toma, HS, Tan, PL, McKusick, VA, Katsanis, N, and Adams, NA. "Bardet-Biedl Syndrome in an African-American patient: should the diagnostic criteria be expanded to include hydrometrocolpos?." Ophthalmic Genet 28.2 (June 2007): 95-99.
PMID
17558852
Source
pubmed
Published In
Ophthalmic Genetics (Informa)
Volume
28
Issue
2
Publish Date
2007
Start Page
95
End Page
99
DOI
10.1080/13816810701209545

An age-old problem.

Authors
Katsanis, N; Rosenberg, SM
MLA Citation
Katsanis, N, and Rosenberg, SM. "An age-old problem." PLoS Genet 3.2 (February 23, 2007): e37-.
PMID
17319751
Source
pubmed
Published In
PLoS genetics
Volume
3
Issue
2
Publish Date
2007
Start Page
e37
DOI
10.1371/journal.pgen.0030037

The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation.

Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal malformation syndrome characterized by renal cystic dysplasia, central nervous system malformations (typically, posterior occipital encephalocele), and hepatic developmental defects. Two MKS genes, MKS1 and MKS3, have been identified recently. The present study describes the cellular, sub-cellular and functional characterization of the novel proteins, MKS1 and meckelin, encoded by these genes. In situ hybridization studies for MKS3 in early human embryos showed transcript localizations in agreement with the tissue phenotype of MKS patients. Both MKS proteins predominantly localized to epithelial cells, including proximal renal tubules and biliary epithelial cells. MKS1 localized to basal bodies, while meckelin localized both to the primary cilium and to the plasma membrane in ciliated cell-lines and primary cells. Meckelin protein with the Q376P missense mutation was unable to localize at the cell membrane. siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated epithelial cell-line blocked centriole migration to the apical membrane and consequent formation of the primary cilium. Co-immunoprecipitation experiments show that wild-type meckelin and MKS1 interact and, in three-dimensional tissue culture assays, epithelial branching morphogenesis was severely impaired. These results suggest that MKS proteins mediate a fundamental developmental stage of ciliary formation and epithelial morphogenesis.

Authors
Dawe, HR; Smith, UM; Cullinane, AR; Gerrelli, D; Cox, P; Badano, JL; Blair-Reid, S; Sriram, N; Katsanis, N; Attie-Bitach, T; Afford, SC; Copp, AJ; Kelly, DA; Gull, K; Johnson, CA
MLA Citation
Dawe, HR, Smith, UM, Cullinane, AR, Gerrelli, D, Cox, P, Badano, JL, Blair-Reid, S, Sriram, N, Katsanis, N, Attie-Bitach, T, Afford, SC, Copp, AJ, Kelly, DA, Gull, K, and Johnson, CA. "The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation." Hum Mol Genet 16.2 (January 15, 2007): 173-186.
PMID
17185389
Source
pubmed
Published In
Human Molecular Genetics
Volume
16
Issue
2
Publish Date
2007
Start Page
173
End Page
186
DOI
10.1093/hmg/ddl459

Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive ciliopathy characterized by progressive retinal degeneration, obesity, cognitive impairment, polydactyly, and kidney anomalies. The disorder is genetically heterogeneous, with 11 BBS genes identified to date, which account for ~70% of affected families. We have combined single-nucleotide-polymorphism array homozygosity mapping with in silico analysis to identify a new BBS gene, BBS12. Patients from two Gypsy families were homozygous and haploidentical in a 6-Mb region of chromosome 4q27. FLJ35630 was selected as a candidate gene, because it was predicted to encode a protein with similarity to members of the type II chaperonin superfamily, which includes BBS6 and BBS10. We found pathogenic mutations in both Gypsy families, as well as in 14 other families of various ethnic backgrounds, indicating that BBS12 accounts for approximately 5% of all BBS cases. BBS12 is vertebrate specific and, together with BBS6 and BBS10, defines a novel branch of the type II chaperonin superfamily. These three genes are characterized by unusually rapid evolution and are likely to perform ciliary functions specific to vertebrates that are important in the pathophysiology of the syndrome, and together they account for about one-third of the total BBS mutational load. Consistent with this notion, suppression of each family member in zebrafish yielded gastrulation-movement defects characteristic of other BBS morphants, whereas simultaneous suppression of all three members resulted in severely affected embryos, possibly hinting at partial functional redundancy within this protein family.

Authors
Stoetzel, C; Muller, J; Laurier, V; Davis, EE; Zaghloul, NA; Vicaire, S; Jacquelin, C; Plewniak, F; Leitch, CC; Sarda, P; Hamel, C; de Ravel, TJL; Lewis, RA; Friederich, E; Thibault, C; Danse, J-M; Verloes, A; Bonneau, D; Katsanis, N; Poch, O; Mandel, J-L; Dollfus, H
MLA Citation
Stoetzel, C, Muller, J, Laurier, V, Davis, EE, Zaghloul, NA, Vicaire, S, Jacquelin, C, Plewniak, F, Leitch, CC, Sarda, P, Hamel, C, de Ravel, TJL, Lewis, RA, Friederich, E, Thibault, C, Danse, J-M, Verloes, A, Bonneau, D, Katsanis, N, Poch, O, Mandel, J-L, and Dollfus, H. "Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome." Am J Hum Genet 80.1 (January 2007): 1-11.
PMID
17160889
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
80
Issue
1
Publish Date
2007
Start Page
1
End Page
11
DOI
10.1086/510256

Population bottlenecks as a potential major shaping force of human genome architecture

The modern synthetic view of human evolution proposes that the fixation of novel mutations is driven by the balance among selective advantage, selective disadvantage, and genetic drift. When considering the global architecture of the human genome, the same model can be applied to understanding the rapid acquisition and proliferation of exogenous DNA. To explore the evolutionary forces that might have morphed human genome architecture, we investigated the origin, composition, and functional potential of numts (nuclear mitochondrial pseudogenes), partial copies of the mitochondrial genome found abundantly in chromosomal DNA. Our data indicate that these elements are unlikely to be advantageous, since they possess no gross positional, transcriptional, or translational features that might indicate beneficial functionality subsequent to integration. Using sequence analysis and fossil dating, we also show a probable burst of integration of numts in the primate lineage that centers on the prosimian-anthropoid split, mimics closely the temporal distribution of Alu and processed pseudogene acquisition, and coincides with the major climatic change at the Paleocene-Eocene boundary. We therefore propose a model according to which the gross architecture and repeat distribution of the human genome can be largely accounted for by a population bottleneck early in the anthropoid lineage and subsequent effectively neutral fixation of repetitive DNA, rather than positive selection or unusual insertion pressures. © 2007 Gherman et al.

Authors
Gherman, A; Chen, PE; Teslovich, TM; Stankiewicz, P; Withers, M; Kashuk, CS; Chakravarti, A; Lupski, JR; Cutler, DJ; Katsanis, N
MLA Citation
Gherman, A, Chen, PE, Teslovich, TM, Stankiewicz, P, Withers, M, Kashuk, CS, Chakravarti, A, Lupski, JR, Cutler, DJ, and Katsanis, N. "Population bottlenecks as a potential major shaping force of human genome architecture." PLoS Genetics 3.7 (2007): 1223-1231.
Source
scival
Published In
PLoS genetics
Volume
3
Issue
7
Publish Date
2007
Start Page
1223
End Page
1231
DOI
10.1371/journal.pgen.0030119

An age-old problem

Authors
Katsanis, N; Rosenberg, SM
MLA Citation
Katsanis, N, and Rosenberg, SM. "An age-old problem." PLoS Genetics 3.2 (2007): 0159-0160.
Source
scival
Published In
PLoS genetics
Volume
3
Issue
2
Publish Date
2007
Start Page
0159
End Page
0160
DOI
10.1371/journal.pgen.0030037

The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia.

Authors
Gherman, A; Davis, EE; Katsanis, N
MLA Citation
Gherman, A, Davis, EE, and Katsanis, N. "The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia." Nat Genet 38.9 (September 2006): 961-962. (Letter)
PMID
16940995
Source
pubmed
Published In
Nature Genetics
Volume
38
Issue
9
Publish Date
2006
Start Page
961
End Page
962
DOI
10.1038/ng0906-961

Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity.

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.

Authors
Eichers, ER; Abd-El-Barr, MM; Paylor, R; Lewis, RA; Bi, W; Lin, X; Meehan, TP; Stockton, DW; Wu, SM; Lindsay, E; Justice, MJ; Beales, PL; Katsanis, N; Lupski, JR
MLA Citation
Eichers, ER, Abd-El-Barr, MM, Paylor, R, Lewis, RA, Bi, W, Lin, X, Meehan, TP, Stockton, DW, Wu, SM, Lindsay, E, Justice, MJ, Beales, PL, Katsanis, N, and Lupski, JR. "Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity." Hum Genet 120.2 (September 2006): 211-226.
PMID
16794820
Source
pubmed
Published In
Human Genetics
Volume
120
Issue
2
Publish Date
2006
Start Page
211
End Page
226
DOI
10.1007/s00439-006-0197-y

The emerging complexity of the vertebrate cilium: new functional roles for an ancient organelle.

Cilia and flagella are found on the surface of a strikingly diverse range of cell types. These intriguing organelles, with their unique and highly adapted protein transport machinery, have been studied extensively in the context of cellular locomotion, sexual reproduction, or fluid propulsion. However, recent studies are beginning to show that in vertebrates particularly, cilia have been recruited to perform additional developmental and homeostatic roles. Here, we review advances in deciphering the functional components of cilia, and we explore emerging trends that implicate ciliary proteins in signal transduction and morphogenetic pathways.

Authors
Davis, EE; Brueckner, M; Katsanis, N
MLA Citation
Davis, EE, Brueckner, M, and Katsanis, N. "The emerging complexity of the vertebrate cilium: new functional roles for an ancient organelle." Dev Cell 11.1 (July 2006): 9-19. (Review)
PMID
16824949
Source
pubmed
Published In
Developmental Cell
Volume
11
Issue
1
Publish Date
2006
Start Page
9
End Page
19
DOI
10.1016/j.devcel.2006.06.009

Life without centrioles: cilia in the spotlight.

Centrioles are critical cellular components that form the architectural core of both centrosomes and basal bodies, the nucleating structures of cilia. New work, including a study in this issue (), highlights the unexpected finding that lack of centrioles does not impede development in the fruit fly. Rather, flies reach maturity but then die because their sensory neurons lack cilia.

Authors
Badano, JL; Katsanis, N
MLA Citation
Badano, JL, and Katsanis, N. "Life without centrioles: cilia in the spotlight." Cell 125.7 (June 30, 2006): 1228-1230.
PMID
16814708
Source
pubmed
Published In
Cell
Volume
125
Issue
7
Publish Date
2006
Start Page
1228
End Page
1230
DOI
10.1016/j.cell.2006.06.013

BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.

Authors
Stoetzel, C; Laurier, V; Davis, EE; Muller, J; Rix, S; Badano, JL; Leitch, CC; Salem, N; Chouery, E; Corbani, S; Jalk, N; Vicaire, S; Sarda, P; Hamel, C; Lacombe, D; Holder, M; Odent, S; Holder, S; Brooks, AS; Elcioglu, NH; Silva, ED; Rossillion, B; Sigaudy, S; de Ravel, TJL; Lewis, RA; Leheup, B; Verloes, A; Amati-Bonneau, P; Mégarbané, A; Poch, O; Bonneau, D; Beales, PL; Mandel, J-L; Katsanis, N; Dollfus, H
MLA Citation
Stoetzel, C, Laurier, V, Davis, EE, Muller, J, Rix, S, Badano, JL, Leitch, CC, Salem, N, Chouery, E, Corbani, S, Jalk, N, Vicaire, S, Sarda, P, Hamel, C, Lacombe, D, Holder, M, Odent, S, Holder, S, Brooks, AS, Elcioglu, NH, Silva, ED, Rossillion, B, Sigaudy, S, de Ravel, TJL, Lewis, RA, Leheup, B, Verloes, A, Amati-Bonneau, P, Mégarbané, A, Poch, O, Bonneau, D, Beales, PL, Mandel, J-L, Katsanis, N, and Dollfus, H. "BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus." Nat Genet 38.5 (May 2006): 521-524.
PMID
16582908
Source
pubmed
Published In
Nature Genetics
Volume
38
Issue
5
Publish Date
2006
Start Page
521
End Page
524
DOI
10.1038/ng1771

Ciliary proteins and exencephaly.

Authors
Katsanis, N
MLA Citation
Katsanis, N. "Ciliary proteins and exencephaly." Nat Genet 38.2 (February 2006): 135-136.
PMID
16444248
Source
pubmed
Published In
Nature Genetics
Volume
38
Issue
2
Publish Date
2006
Start Page
135
End Page
136
DOI
10.1038/ng0206-135

Dissection of epistasis in oligogenic Bardet-Biedl syndrome.

Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging. Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet-Biedl syndrome (BBS), a pleiotropic, oligogenic disorder. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.

Authors
Badano, JL; Leitch, CC; Ansley, SJ; May-Simera, H; Lawson, S; Lewis, RA; Beales, PL; Dietz, HC; Fisher, S; Katsanis, N
MLA Citation
Badano, JL, Leitch, CC, Ansley, SJ, May-Simera, H, Lawson, S, Lewis, RA, Beales, PL, Dietz, HC, Fisher, S, and Katsanis, N. "Dissection of epistasis in oligogenic Bardet-Biedl syndrome." Nature 439.7074 (January 19, 2006): 326-330.
PMID
16327777
Source
pubmed
Published In
Nature
Volume
439
Issue
7074
Publish Date
2006
Start Page
326
End Page
330
DOI
10.1038/nature04370

Erratum: BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus (Nature Genetics (2006) 38 (521-524))

Authors
Stoetzel, C; Laurier, V; Davis, EE; Muller, J; Rix, S; Badano, JL; Leitch, CC; Salem, N; Chouery, E; Corbani, S; Jalk, N; Vicaire, S; Sarda, P; Hamel, C; Lacombe, D; Holder, M; Odent, S; Holder, S; Brooks, AS; Elcioglu, NH; Silva, ED; Rossillion, B; Sigaudy, S; Ravel, TJLD; Lewis, RA; Leheup, B; Verloes, A; Amati-Bonneau, P; Mégarbané, A; Poch, O; Bonneau, D; Beales, PL; Mandel, JL; Katsanis, N; Dollfus, H
MLA Citation
Stoetzel, C, Laurier, V, Davis, EE, Muller, J, Rix, S, Badano, JL, Leitch, CC, Salem, N, Chouery, E, Corbani, S, Jalk, N, Vicaire, S, Sarda, P, Hamel, C, Lacombe, D, Holder, M, Odent, S, Holder, S, Brooks, AS, Elcioglu, NH, Silva, ED, Rossillion, B, Sigaudy, S, Ravel, TJLD, Lewis, RA, Leheup, B, Verloes, A, Amati-Bonneau, P, Mégarbané, A, Poch, O, Bonneau, D, Beales, PL, Mandel, JL, Katsanis, N, and Dollfus, H. "Erratum: BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus (Nature Genetics (2006) 38 (521-524))." Nature Genetics 38.6 (2006): 727--.
Source
scival
Published In
Nature Genetics
Volume
38
Issue
6
Publish Date
2006
Start Page
727-
DOI
10.1038/ng0606-721

The ciliopathies: an emerging class of human genetic disorders.

Cilia and flagella are ancient, evolutionarily conserved organelles that project from cell surfaces to perform diverse biological roles, including whole-cell locomotion; movement of fluid; chemo-, mechano-, and photosensation; and sexual reproduction. Consistent with their stringent evolutionary conservation, defects in cilia are associated with a range of human diseases, such as primary ciliary dyskinesia, hydrocephalus, polycystic liver and kidney disease, and some forms of retinal degeneration. Recent evidence indicates that ciliary defects can lead to a broader set of developmental and adult phenotypes, with mutations in ciliary proteins now associated with nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome. The molecular data linking seemingly unrelated clinical entities are beginning to highlight a common theme, where defects in ciliary structure and function can lead to a predictable phenotypic pattern that has potentially predictive and therapeutic value.

Authors
Badano, JL; Mitsuma, N; Beales, PL; Katsanis, N
MLA Citation
Badano, JL, Mitsuma, N, Beales, PL, and Katsanis, N. "The ciliopathies: an emerging class of human genetic disorders." Annu Rev Genomics Hum Genet 7 (2006): 125-148. (Review)
PMID
16722803
Source
pubmed
Published In
Annual Review of Genomics and Human Genetics
Volume
7
Publish Date
2006
Start Page
125
End Page
148
DOI
10.1146/annurev.genom.7.080505.115610

Small molecule intervention in microtubule-associated human disease.

Microtubules are essential for a number of cellular processes that include the transport of intracellular cargo or organelles across long distances and the assembly of the mitotic spindle. The identification of numerous microtubule-associated proteins and the progressive elucidation of the mechanisms of microtubule assembly and transport are beginning to have a profound impact on the study and treatment of human genetic disease. A number of seemingly unrelated phenotypes have now been linked to microtubular dysfunction, especially in systems dependent heavily on microtubule-based transport, such as neurons and ciliated cells. In parallel, the association of microtubule transport defects with human genetic disease has led to the realization that targeting various aspects of microtubular biology with small molecules might offer new therapeutic paradigms, including the development of new therapeutic utility for seemingly old drugs. In this review, we discuss the use of small molecules in the investigation of microtubule-associated processes and particularly the screens of chemical compound libraries for the identification of lead compounds with potential utility in microtubule-associated disease processes.

Authors
Gerdes, JM; Katsanis, N
MLA Citation
Gerdes, JM, and Katsanis, N. "Small molecule intervention in microtubule-associated human disease." Hum Mol Genet 14 Spec No. 2 (October 15, 2005): R291-R300. (Review)
PMID
16244328
Source
pubmed
Published In
Human Molecular Genetics
Volume
14 Spec No. 2
Publish Date
2005
Start Page
R291
End Page
R300
DOI
10.1093/hmg/ddi269

Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates.

The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation. Here we show that mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles. Furthermore, we identify genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. We also show that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggest that cilia are intrinsically involved in PCP processes.

Authors
Ross, AJ; May-Simera, H; Eichers, ER; Kai, M; Hill, J; Jagger, DJ; Leitch, CC; Chapple, JP; Munro, PM; Fisher, S; Tan, PL; Phillips, HM; Leroux, MR; Henderson, DJ; Murdoch, JN; Copp, AJ; Eliot, M-M; Lupski, JR; Kemp, DT; Dollfus, H; Tada, M; Katsanis, N; Forge, A; Beales, PL
MLA Citation
Ross, AJ, May-Simera, H, Eichers, ER, Kai, M, Hill, J, Jagger, DJ, Leitch, CC, Chapple, JP, Munro, PM, Fisher, S, Tan, PL, Phillips, HM, Leroux, MR, Henderson, DJ, Murdoch, JN, Copp, AJ, Eliot, M-M, Lupski, JR, Kemp, DT, Dollfus, H, Tada, M, Katsanis, N, Forge, A, and Beales, PL. "Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates." Nat Genet 37.10 (October 2005): 1135-1140.
PMID
16170314
Source
pubmed
Published In
Nature Genetics
Volume
37
Issue
10
Publish Date
2005
Start Page
1135
End Page
1140
DOI
10.1038/ng1644

Microtubule transport defects in neurological and ciliary disease.

Microtubules are primarily responsible for facilitating long-distance transport of both proteins and organelles. Given the critical role of this process in cellular function, it is not surprising that perturbation of microtubule-based transport can lead to diverse phenotypes in humans, including cancer and neurodegenerative disorders such as Alzheimer or Huntington disease. Recent investigations have also indicated that defects in specialized microtubule-based transport systems, such as mutations affecting the transport of protein particles along the length of cilia (intraflagellar transport) can cause retinal dystrophy, polycystic kidney disease or more complex syndromic phenotypes, such as Bardet-Biedl syndrome. In this review, we discuss recent findings implicating defects in microtubule-associated transport and motor proteins in a variety of diseases, particularly the role of defective microtubular transport in neurological and ciliary disease. These defects frequently display phenotypic consequences that manifest as human disease yet do not cause organismal lethality.

Authors
Gerdes, JM; Katsanis, N
MLA Citation
Gerdes, JM, and Katsanis, N. "Microtubule transport defects in neurological and ciliary disease." Cell Mol Life Sci 62.14 (July 2005): 1556-1570. (Review)
PMID
15924265
Source
pubmed
Published In
Cellular and Molecular Life Sciences
Volume
62
Issue
14
Publish Date
2005
Start Page
1556
End Page
1570
DOI
10.1007/s00018-005-5007-5

A manually curated functional annotation of the human X chromosome.

Authors
Harsha, HC; Suresh, S; Amanchy, R; Deshpande, N; Shanker, K; Yatish, AJ; Muthusamy, B; Vrushabendra, BM; Rashmi, BP; Chandrika, KN; Padma, N; Sharma, S; Badano, JL; Ramya, MA; Shivashankar, HN; Peri, S; Choudhury, DR; Kavitha, MP; Saravana, R; Niranjan, V; Gandhi, TKB; Ghosh, N; Chandran, S; Menezes, M; Joy, M; Mohan, SS; Katsanis, N; Deshpande, KS; Raghothama, C; Prasad, CK; Pandey, A
MLA Citation
Harsha, HC, Suresh, S, Amanchy, R, Deshpande, N, Shanker, K, Yatish, AJ, Muthusamy, B, Vrushabendra, BM, Rashmi, BP, Chandrika, KN, Padma, N, Sharma, S, Badano, JL, Ramya, MA, Shivashankar, HN, Peri, S, Choudhury, DR, Kavitha, MP, Saravana, R, Niranjan, V, Gandhi, TKB, Ghosh, N, Chandran, S, Menezes, M, Joy, M, Mohan, SS, Katsanis, N, Deshpande, KS, Raghothama, C, Prasad, CK, and Pandey, A. "A manually curated functional annotation of the human X chromosome." Nat Genet 37.4 (April 2005): 331-332. (Letter)
PMID
15800640
Source
pubmed
Published In
Nature Genetics
Volume
37
Issue
4
Publish Date
2005
Start Page
331
End Page
332
DOI
10.1038/ng0405-331

MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis.

Chaperonins are multisubunit, cylinder-shaped molecular chaperones involved in folding newly synthesized polypeptides. Here we show that MKKS/BBS6, one of several proteins associated with Bardet-Biedl syndrome (BBS), is a Group II chaperonin-like protein that has evolved recently in animals from a subunit of the eukaryotic chaperonin CCT/TRiC, and diverged rapidly to acquire distinct functions. Unlike other chaperonins, cytosolic BBS6 does not oligomerize, and the majority of BBS6 resides within the pericentriolar material (PCM), a proteinaceous tube surrounding centrioles. During interphase, BBS6 is confined to the lateral surfaces of the PCM but during mitosis it relocalizes throughout the PCM and is found at the intercellular bridge. Its predicted substrate-binding apical domain is sufficient for centrosomal association, and several patient-derived mutations in this domain cause mislocalization of BBS6. Consistent with an important centrosomal function, silencing of the BBS6 transcript by RNA interference in different cell types leads to multinucleate and multicentrosomal cells with cytokinesis defects. The restricted tissue distribution of BBS6 further suggests that it may play important roles in ciliated epithelial tissues, which is consistent with the probable functions of BBS proteins in basal bodies (modified centrioles) and cilia. Our findings provide the first insight into the nature and cellular function of BBS6, and shed light on the potential causes of several ailments, including obesity, retinal degeneration, kidney dysfunction and congenital heart disease.

Authors
Kim, JC; Ou, YY; Badano, JL; Esmail, MA; Leitch, CC; Fiedrich, E; Beales, PL; Archibald, JM; Katsanis, N; Rattner, JB; Leroux, MR
MLA Citation
Kim, JC, Ou, YY, Badano, JL, Esmail, MA, Leitch, CC, Fiedrich, E, Beales, PL, Archibald, JM, Katsanis, N, Rattner, JB, and Leroux, MR. "MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet-Biedl syndrome, is a novel centrosomal component required for cytokinesis." J Cell Sci 118.Pt 5 (March 1, 2005): 1007-1020.
PMID
15731008
Source
pubmed
Published In
Journal of cell science
Volume
118
Issue
Pt 5
Publish Date
2005
Start Page
1007
End Page
1020
DOI
10.1242/jcs.01676

The centrosome in human genetic disease.

The centrosome is an indispensable component of the cell-cycle machinery of eukaryotic cells, and the perturbation of core centrosomal or centrosome-associated proteins is linked to cell-cycle misregulation and cancer. Recent work has expanded our understanding of the functional complexity and importance of this organelle. The centrosomal localization of proteins that are involved in human genetic disease, and the identification of novel centrosome-associated proteins, has shown that numerous, seemingly unrelated, cellular processes can be perturbed by centrosomal dysfunction. Here, we review the mechanistic relationship between human disease phenotypes and the function of the centrosome, and describe some of the newly-appreciated functions of this organelle in animal cells.

Authors
Badano, JL; Teslovich, TM; Katsanis, N
MLA Citation
Badano, JL, Teslovich, TM, and Katsanis, N. "The centrosome in human genetic disease." Nat Rev Genet 6.3 (March 2005): 194-205. (Review)
PMID
15738963
Source
pubmed
Published In
Nature Reviews Genetics
Volume
6
Issue
3
Publish Date
2005
Start Page
194
End Page
205
DOI
10.1038/nrg1557

A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.

We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor beta receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFbeta signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling. These data definitively implicate perturbation of TGFbeta signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.

Authors
Loeys, BL; Chen, J; Neptune, ER; Judge, DP; Podowski, M; Holm, T; Meyers, J; Leitch, CC; Katsanis, N; Sharifi, N; Xu, FL; Myers, LA; Spevak, PJ; Cameron, DE; De Backer, J; Hellemans, J; Chen, Y; Davis, EC; Webb, CL; Kress, W; Coucke, P; Rifkin, DB; De Paepe, AM; Dietz, HC
MLA Citation
Loeys, BL, Chen, J, Neptune, ER, Judge, DP, Podowski, M, Holm, T, Meyers, J, Leitch, CC, Katsanis, N, Sharifi, N, Xu, FL, Myers, LA, Spevak, PJ, Cameron, DE, De Backer, J, Hellemans, J, Chen, Y, Davis, EC, Webb, CL, Kress, W, Coucke, P, Rifkin, DB, De Paepe, AM, and Dietz, HC. "A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2." Nat Genet 37.3 (March 2005): 275-281.
PMID
15731757
Source
pubmed
Published In
Nature Genetics
Volume
37
Issue
3
Publish Date
2005
Start Page
275
End Page
281
DOI
10.1038/ng1511

Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study.

Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

Authors
Moore, SJ; Green, JS; Fan, Y; Bhogal, AK; Dicks, E; Fernandez, BA; Stefanelli, M; Murphy, C; Cramer, BC; Dean, JCS; Beales, PL; Katsanis, N; Bassett, AS; Davidson, WS; Parfrey, PS
MLA Citation
Moore, SJ, Green, JS, Fan, Y, Bhogal, AK, Dicks, E, Fernandez, BA, Stefanelli, M, Murphy, C, Cramer, BC, Dean, JCS, Beales, PL, Katsanis, N, Bassett, AS, Davidson, WS, and Parfrey, PS. "Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study." Am J Med Genet A 132A.4 (February 1, 2005): 352-360.
PMID
15637713
Source
pubmed
Published In
American Journal of Medical Genetics Part A
Volume
132A
Issue
4
Publish Date
2005
Start Page
352
End Page
360
DOI
10.1002/ajmg.a.30406

Erratum: Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates (Nature Genetics (2005) 37 (1135-1140))

Authors
Ross, AJ; May-Simera, H; Eichers, ER; Kai, M; Hill, J; Jagger, DJ; Leitch, CC; Chapple, JP; Munro, PM; Fisher, S; Tan, PL; Phillips, HM; Leroux, MR; Henderson, DJ; Murdoch, JN; Copp, AJ; Eliot, MM; Lupski, JR; Kemp, DT; Dollfus, H; Tada, M; Katsanis, N; Forge, A; Beales, PL
MLA Citation
Ross, AJ, May-Simera, H, Eichers, ER, Kai, M, Hill, J, Jagger, DJ, Leitch, CC, Chapple, JP, Munro, PM, Fisher, S, Tan, PL, Phillips, HM, Leroux, MR, Henderson, DJ, Murdoch, JN, Copp, AJ, Eliot, MM, Lupski, JR, Kemp, DT, Dollfus, H, Tada, M, Katsanis, N, Forge, A, and Beales, PL. "Erratum: Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates (Nature Genetics (2005) 37 (1135-1140))." Nature Genetics 37.12 (2005): 1381--.
Source
scival
Published In
Nature Genetics
Volume
37
Issue
12
Publish Date
2005
Start Page
1381-
DOI
10.1038/ng1205-1381b

Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome.

RAB, ADP-ribosylation factors (ARFs) and ARF-like (ARL) proteins belong to the Ras superfamily of small GTP-binding proteins and are essential for various membrane-associated intracellular trafficking processes. None of the approximately 50 known members of this family are linked to human disease. Using a bioinformatic screen for ciliary genes in combination with mutational analyses, we identified ARL6 as the gene underlying Bardet-Biedl syndrome type 3, a multisystemic disorder characterized by obesity, blindness, polydactyly, renal abnormalities and cognitive impairment. We uncovered four different homozygous substitutions in ARL6 in four unrelated families affected with Bardet-Biedl syndrome, two of which disrupt a threonine residue important for GTP binding and function of several related small GTP-binding proteins. Analysis of the Caenorhabditis elegans ARL6 homolog indicates that it is specifically expressed in ciliated cells, and that, in addition to the postulated cytoplasmic functions of ARL proteins, it undergoes intraflagellar transport. These findings implicate a small GTP-binding protein in ciliary transport and the pathogenesis of a pleiotropic disorder.

Authors
Fan, Y; Esmail, MA; Ansley, SJ; Blacque, OE; Boroevich, K; Ross, AJ; Moore, SJ; Badano, JL; May-Simera, H; Compton, DS; Green, JS; Lewis, RA; van Haelst, MM; Parfrey, PS; Baillie, DL; Beales, PL; Katsanis, N; Davidson, WS; Leroux, MR
MLA Citation
Fan, Y, Esmail, MA, Ansley, SJ, Blacque, OE, Boroevich, K, Ross, AJ, Moore, SJ, Badano, JL, May-Simera, H, Compton, DS, Green, JS, Lewis, RA, van Haelst, MM, Parfrey, PS, Baillie, DL, Beales, PL, Katsanis, N, Davidson, WS, and Leroux, MR. "Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome." Nat Genet 36.9 (September 2004): 989-993.
PMID
15314642
Source
pubmed
Published In
Nature Genetics
Volume
36
Issue
9
Publish Date
2004
Start Page
989
End Page
993
DOI
10.1038/ng1414

Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse.

Defects in cilia are associated with several human disorders, including Kartagener syndrome, polycystic kidney disease, nephronophthisis and hydrocephalus. We proposed that the pleiotropic phenotype of Bardet-Biedl syndrome (BBS), which encompasses retinal degeneration, truncal obesity, renal and limb malformations and developmental delay, is due to dysfunction of basal bodies and cilia. Here we show that individuals with BBS have partial or complete anosmia. To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, we examined mice with deletions of Bbs1 or Bbs4. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement.

Authors
Kulaga, HM; Leitch, CC; Eichers, ER; Badano, JL; Lesemann, A; Hoskins, BE; Lupski, JR; Beales, PL; Reed, RR; Katsanis, N
MLA Citation
Kulaga, HM, Leitch, CC, Eichers, ER, Badano, JL, Lesemann, A, Hoskins, BE, Lupski, JR, Beales, PL, Reed, RR, and Katsanis, N. "Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse." Nat Genet 36.9 (September 2004): 994-998.
PMID
15322545
Source
pubmed
Published In
Nature Genetics
Volume
36
Issue
9
Publish Date
2004
Start Page
994
End Page
998
DOI
10.1038/ng1418

Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous developmental disorder whose molecular basis is largely unknown. Here, we show that mutations in the Caenorhabditis elegans bbs-7 and bbs-8 genes cause structural and functional defects in cilia. C. elegans BBS proteins localize predominantly at the base of cilia, and like proteins involved in intraflagellar transport (IFT), a process necessary for cilia biogenesis and maintenance, move bidirectionally along the ciliary axoneme. Importantly, we demonstrate that BBS-7 and BBS-8 are required for the normal localization/motility of the IFT proteins OSM-5/Polaris and CHE-11, and to a notably lesser extent, CHE-2. We propose that BBS proteins play important, selective roles in the assembly and/or function of IFT particle components. Our findings also suggest that some of the cardinal and secondary symptoms of BBS, such as obesity, diabetes, cardiomyopathy, and learning defects may result from cilia dysfunction.

Authors
Blacque, OE; Reardon, MJ; Li, C; McCarthy, J; Mahjoub, MR; Ansley, SJ; Badano, JL; Mah, AK; Beales, PL; Davidson, WS; Johnsen, RC; Audeh, M; Plasterk, RHA; Baillie, DL; Katsanis, N; Quarmby, LM; Wicks, SR; Leroux, MR
MLA Citation
Blacque, OE, Reardon, MJ, Li, C, McCarthy, J, Mahjoub, MR, Ansley, SJ, Badano, JL, Mah, AK, Beales, PL, Davidson, WS, Johnsen, RC, Audeh, M, Plasterk, RHA, Baillie, DL, Katsanis, N, Quarmby, LM, Wicks, SR, and Leroux, MR. "Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport." Genes Dev 18.13 (July 1, 2004): 1630-1642.
PMID
15231740
Source
pubmed
Published In
Genes & development
Volume
18
Issue
13
Publish Date
2004
Start Page
1630
End Page
1642
DOI
10.1101/gad.1194004

Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene.

Cilia and flagella are microtubule-based structures nucleated by modified centrioles termed basal bodies. These biochemically complex organelles have more than 250 and 150 polypeptides, respectively. To identify the proteins involved in ciliary and basal body biogenesis and function, we undertook a comparative genomics approach that subtracted the nonflagellated proteome of Arabidopsis from the shared proteome of the ciliated/flagellated organisms Chlamydomonas and human. We identified 688 genes that are present exclusively in organisms with flagella and basal bodies and validated these data through a series of in silico, in vitro, and in vivo studies. We then applied this resource to the study of human ciliation disorders and have identified BBS5, a novel gene for Bardet-Biedl syndrome. We show that this novel protein localizes to basal bodies in mouse and C. elegans, is under the regulatory control of daf-19, and is necessary for the generation of both cilia and flagella.

Authors
Li, JB; Gerdes, JM; Haycraft, CJ; Fan, Y; Teslovich, TM; May-Simera, H; Li, H; Blacque, OE; Li, L; Leitch, CC; Lewis, RA; Green, JS; Parfrey, PS; Leroux, MR; Davidson, WS; Beales, PL; Guay-Woodford, LM; Yoder, BK; Stormo, GD; Katsanis, N; Dutcher, SK
MLA Citation
Li, JB, Gerdes, JM, Haycraft, CJ, Fan, Y, Teslovich, TM, May-Simera, H, Li, H, Blacque, OE, Li, L, Leitch, CC, Lewis, RA, Green, JS, Parfrey, PS, Leroux, MR, Davidson, WS, Beales, PL, Guay-Woodford, LM, Yoder, BK, Stormo, GD, Katsanis, N, and Dutcher, SK. "Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene." Cell 117.4 (May 14, 2004): 541-552.
PMID
15137946
Source
pubmed
Published In
Cell
Volume
117
Issue
4
Publish Date
2004
Start Page
541
End Page
552

The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.

BBS4 is one of several proteins that cause Bardet-Biedl syndrome (BBS), a multisystemic disorder of genetic and clinical complexity. Here we show that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit PCM1 (pericentriolar material 1 protein) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division and apoptotic cell death. Expression of two truncated forms of BBS4 that are similar to those found in some individuals with BBS had a similar effect on PCM1 and microtubules. Our findings indicate that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes and retinal degeneration.

Authors
Kim, JC; Badano, JL; Sibold, S; Esmail, MA; Hill, J; Hoskins, BE; Leitch, CC; Venner, K; Ansley, SJ; Ross, AJ; Leroux, MR; Katsanis, N; Beales, PL
MLA Citation
Kim, JC, Badano, JL, Sibold, S, Esmail, MA, Hill, J, Hoskins, BE, Leitch, CC, Venner, K, Ansley, SJ, Ross, AJ, Leroux, MR, Katsanis, N, and Beales, PL. "The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression." Nat Genet 36.5 (May 2004): 462-470.
PMID
15107855
Source
pubmed
Published In
Nature Genetics
Volume
36
Issue
5
Publish Date
2004
Start Page
462
End Page
470
DOI
10.1038/ng1352

The oligogenic properties of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS: OMIM 209900) is a rare developmental disorder that exhibits significant clinical and genetic heterogeneity. Although modeled initially as a purely recessive trait, recent data have unmasked an oligogenic mode of disease transmission, in which mutations at different BBS loci can interact genetically in some families to cause and/or modify the phenotype. Here, I will review and discuss recent advances in elucidating both genetic and cellular aspects of this phenotype and their potential application in understanding the genetic basis of phenotypic variability and oligogenic inheritance.

Authors
Katsanis, N
MLA Citation
Katsanis, N. "The oligogenic properties of Bardet-Biedl syndrome." Hum Mol Genet 13 Spec No 1 (April 1, 2004): R65-R71. (Review)
PMID
14976158
Source
pubmed
Published In
Human Molecular Genetics
Volume
13 Spec No 1
Publish Date
2004
Start Page
R65
End Page
R71
DOI
10.1093/hmg/ddh092

Triallelic inheritance: a bridge between Mendelian and multifactorial traits.

The increasing identification of disease genes is revealing a growing number of traits that fail to conform to traditional Mendelian paradigms, thereby creating new challenges to both genetic investigators and clinicians. Bardet-Biedl syndrome (BBS) is one such disorder that has helped to define 'oligogenic' inheritance, a term that implies that some diseases are not inherited as simple single-gene Mendelian disorders and yet are not classic complex traits, but rather fit a model in which mutations in a small number of genes may interact genetically to manifest the phenotype. BBS is a pleiotropic disorder characterized by postnatal obesity, post-axial polydactyly, and progressive retinal dystrophy. Eight BBS loci have been identified to date and six of these genes have been cloned. Mutation analysis of these BBS genes in a cohort of patients has led to the description of the novel phenomenon of 'triallelic inheritance', wherein families were identified in which three mutations from genes at two different BBS loci segregate with expression of the disease. Modeling the cooperative ability of alleles of different genes at distinct loci to give rise to a particular phenotype will facilitate the understanding of complex multifactorial and polygenic traits.

Authors
Eichers, ER; Lewis, RA; Katsanis, N; Lupski, JR
MLA Citation
Eichers, ER, Lewis, RA, Katsanis, N, and Lupski, JR. "Triallelic inheritance: a bridge between Mendelian and multifactorial traits." Ann Med 36.4 (2004): 262-272.
PMID
15224652
Source
pubmed
Published In
Annals of Medicine (Informa)
Volume
36
Issue
4
Publish Date
2004
Start Page
262
End Page
272

Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized primarily by retinal dystrophy, obesity, polydactyly, renal malformations and learning disabilities. Although five BBS genes have been cloned, the molecular basis of this syndrome remains elusive. Here we show that BBS is probably caused by a defect at the basal body of ciliated cells. We have cloned a new BBS gene, BBS8, which encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In one family, a homozygous null BBS8 mutation leads to BBS with randomization of left-right body axis symmetry, a known defect of the nodal cilium. We have also found that BBS8 localizes specifically to ciliated structures, such as the connecting cilium of the retina and columnar epithelial cells in the lung. In cells, BBS8 localizes to centrosomes and basal bodies and interacts with PCM1, a protein probably involved in ciliogenesis. Finally, we demonstrate that all available Caenorhabditis elegans BBS homologues are expressed exclusively in ciliated neurons, and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport.

Authors
Ansley, SJ; Badano, JL; Blacque, OE; Hill, J; Hoskins, BE; Leitch, CC; Kim, JC; Ross, AJ; Eichers, ER; Teslovich, TM; Mah, AK; Johnsen, RC; Cavender, JC; Lewis, RA; Leroux, MR; Beales, PL; Katsanis, N
MLA Citation
Ansley, SJ, Badano, JL, Blacque, OE, Hill, J, Hoskins, BE, Leitch, CC, Kim, JC, Ross, AJ, Eichers, ER, Teslovich, TM, Mah, AK, Johnsen, RC, Cavender, JC, Lewis, RA, Leroux, MR, Beales, PL, and Katsanis, N. "Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome." Nature 425.6958 (October 9, 2003): 628-633.
PMID
14520415
Source
pubmed
Published In
Nature
Volume
425
Issue
6958
Publish Date
2003
Start Page
628
End Page
633
DOI
10.1038/nature02030

Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.

Bardet-Biedl syndrome (BBS) is a pleiotropic genetic disorder with substantial inter- and intrafamilial variability, that also exhibits remarkable genetic heterogeneity, with seven mapped BBS loci in the human genome. Recent data have demonstrated that BBS may be inherited either as a simple Mendelian recessive or as an oligogenic trait, since mutations at two loci are sometimes required for pathogenesis. This observation suggests that genetic interactions between the different BBS loci may modulate the phenotype, thus contributing to the clinical variability of BBS. We present three families with two mutations in either BBS1 or BBS2, in which some but not all patients carry a third mutation in BBS1, BBS2 or the putative chaperonin BBS6. In each example, the presence of three mutant alleles correlates with a more severe phenotype. For one of the missense alleles, we also demonstrate that the introduction of the mutation in mammalian cells causes a dramatic mislocalization of the protein compared with the wild-type. These data suggest that triallelic mutations are not always necessary for disease manifestation, but might potentiate a phenotype that is caused by two recessive mutations at an independent locus, thus introducing an additional layer of complexity on the genetic modeling of oligogenicity.

Authors
Badano, JL; Kim, JC; Hoskins, BE; Lewis, RA; Ansley, SJ; Cutler, DJ; Castellan, C; Beales, PL; Leroux, MR; Katsanis, N
MLA Citation
Badano, JL, Kim, JC, Hoskins, BE, Lewis, RA, Ansley, SJ, Cutler, DJ, Castellan, C, Beales, PL, Leroux, MR, and Katsanis, N. "Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus." Hum Mol Genet 12.14 (July 15, 2003): 1651-1659.
PMID
12837689
Source
pubmed
Published In
Human Molecular Genetics
Volume
12
Issue
14
Publish Date
2003
Start Page
1651
End Page
1659

Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.

Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis. To date, four of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. We present a comprehensive analysis of the spectrum, distribution, and involvement in non-Mendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicate that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. Consistent with this model, we identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. Moreover, our statistical analyses indicate that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. The distribution of BBS oligogenic alleles also indicates that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other.

Authors
Beales, PL; Badano, JL; Ross, AJ; Ansley, SJ; Hoskins, BE; Kirsten, B; Mein, CA; Froguel, P; Scambler, PJ; Lewis, RA; Lupski, JR; Katsanis, N
MLA Citation
Beales, PL, Badano, JL, Ross, AJ, Ansley, SJ, Hoskins, BE, Kirsten, B, Mein, CA, Froguel, P, Scambler, PJ, Lewis, RA, Lupski, JR, and Katsanis, N. "Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome." Am J Hum Genet 72.5 (May 2003): 1187-1199.
PMID
12677556
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
72
Issue
5
Publish Date
2003
Start Page
1187
End Page
1199
DOI
10.1086/375178

Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder, the primary features of which include obesity, retinal dystrophy, polydactyly, hypogenitalism, learning difficulties, and renal malformations. Conventional linkage and positional cloning have led to the mapping of six BBS loci in the human genome, four of which (BBS1, BBS2, BBS4, and BBS6) have been cloned. Despite these advances, the protein sequences of the known BBS genes have provided little or no insight into their function. To delineate functionally important regions in BBS2, we performed phylogenetic and genomic studies in which we used the human and zebrafish BBS2 peptide sequences to search dbEST and the translation of the draft human genome. We identified two novel genes that we initially named "BBS2L1" and "BBS2L2" and that exhibit modest similarity with two discrete, overlapping regions of BBS2. In the present study, we demonstrate that BBS2L1 mutations cause BBS, thereby defining a novel locus for this syndrome, BBS7, whereas BBS2L2 has been shown independently to be BBS1. The motif-based identification of a novel BBS locus has enabled us to define a potential functional domain that is present in three of the five known BBS proteins and, therefore, is likely to be important in the pathogenesis of this complex syndrome.

Authors
Badano, JL; Ansley, SJ; Leitch, CC; Lewis, RA; Lupski, JR; Katsanis, N
MLA Citation
Badano, JL, Ansley, SJ, Leitch, CC, Lewis, RA, Lupski, JR, and Katsanis, N. "Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2." Am J Hum Genet 72.3 (March 2003): 650-658.
PMID
12567324
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
72
Issue
3
Publish Date
2003
Start Page
650
End Page
658
DOI
10.1086/368204

A computational/functional genomics approach for the enrichment of the retinal transcriptome and the identification of positional candidate retinopathy genes.

Grouping genes by virtue of their sequence similarity, functional association, or spatiotemporal distribution is an important first step in investigating function. Given the recent identification of >30,000 human genes either by analyses of genomic sequence or by derivation/assembly of ESTs, automated means of discerning gene function and association with disease are critical for the efficient processing of this large volume of data. We have designed a series of computational tools to manipulate the EST sequence database (dbEST) to predict EST clusters likely representing genes expressed exclusively or preferentially in a specific tissue. We implemented this tool by extracting 40,000 human retinal ESTs and performing in silico subtraction against 1.4 million human ESTs. This process yielded 925 ESTs likely to be specifically or preferentially expressed in the retina. We mapped all retinal-specific/predominant sequences in the human genome and produced a web-based searchable map of the retina transcriptome, onto which we overlaid the positions of all mapped but uncloned retinopathy genes. This resource has provided positional candidates for 42 of 51 uncloned retinopathies and may expedite substantially the identification of disease-associated genes. More importantly, the ability to systematically group ESTs according to their predicted expression profile is likely to be an important resource for studying gene function in a wide range of tissues and physiological systems and to identify positional candidate genes for human disorders whose phenotypic manifestations are restricted to specific tissues/organs/cell types.

Authors
Katsanis, N; Worley, KC; Gonzalez, G; Ansley, SJ; Lupski, JR
MLA Citation
Katsanis, N, Worley, KC, Gonzalez, G, Ansley, SJ, and Lupski, JR. "A computational/functional genomics approach for the enrichment of the retinal transcriptome and the identification of positional candidate retinopathy genes." Proc Natl Acad Sci U S A 99.22 (October 29, 2002): 14326-14331.
PMID
12391299
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
99
Issue
22
Publish Date
2002
Start Page
14326
End Page
14331
DOI
10.1073/pnas.222409099

Beyond Mendel: an evolving view of human genetic disease transmission.

Methodological and conceptual advances in human genetics have led to the identification of an impressive number of human disease genes. This wealth of information has also revealed that the traditional distinction between Mendelian and complex disorders might sometimes be blurred. Genetic and mutational data on an increasing number of disorders have illustrated how phenotypic effects can result from the combined action of alleles in many genes. In this review, we discuss how an improved understanding of the genetic basis of multilocus inheritance is catalysing the transition from a segmented view of human genetic disease to a conceptual continuum between Mendelian and complex traits.

Authors
Badano, JL; Katsanis, N
MLA Citation
Badano, JL, and Katsanis, N. "Beyond Mendel: an evolving view of human genetic disease transmission." Nat Rev Genet 3.10 (October 2002): 779-789. (Review)
PMID
12360236
Source
pubmed
Published In
Nature Reviews Genetics
Volume
3
Issue
10
Publish Date
2002
Start Page
779
End Page
789
DOI
10.1038/nrg910

BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.

Bardet-Biedl syndrome (BBS) is an uncommon multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction. BBS has been modeled historically as an autosomal recessive trait, under which premise six independent BBS loci (BBS1-BBS6) have been mapped in the human genome. However, extended mutational analyses of BBS2 and BBS6, the first two BBS genes cloned, suggest that BBS exhibits a more complex pattern of inheritance, in which three mutations at two loci simultaneously are necessary and sufficient in some families to manifest the phenotype. We evaluated the spectrum of mutations in the recently identified BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families. Consistent with predictions from previous genetic analyses, our data suggest that mutations in BBS4 contribute to BBS in <3% of affected families. Furthermore, integrated mutational data from all three currently cloned BBS genes raise the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins.

Authors
Katsanis, N; Eichers, ER; Ansley, SJ; Lewis, RA; Kayserili, H; Hoskins, BE; Scambler, PJ; Beales, PL; Lupski, JR
MLA Citation
Katsanis, N, Eichers, ER, Ansley, SJ, Lewis, RA, Kayserili, H, Hoskins, BE, Scambler, PJ, Beales, PL, and Lupski, JR. "BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance." Am J Hum Genet 71.1 (July 2002): 22-29.
PMID
12016587
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
71
Issue
1
Publish Date
2002
Start Page
22
End Page
29
DOI
10.1086/341031

Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1.

Some isolated populations exhibit an increased prevalence of rare recessive diseases. The island of Newfoundland is a characteristic geographic isolate, settled by a small number of families primarily during the late 1700s and early 1800s. During our studies of this population, we identified a group of families exhibiting a retinal dystrophy reminiscent of retinitis punctata albescens but with a substantially lower age at onset and more-rapid and distinctive progression, a disorder that we termed "Newfoundland rod-cone dystrophy" (NFRCD). The size of one of these families was sufficient to allow us to perform a genomewide screen to map the NFRCD locus. We detected significant linkage to markers on the long arm of chromosome 15, in a region encompassing RLBP1, the gene encoding the cellular retinaldehyde-binding protein. Previously, mutations in RLBP1 have been associated with other retinal dystrophies, leading us to hypothesize that RLBP1 mutations might also cause NFRCD. To test this hypothesis, we sequenced all coding exons and splice junctions of RLBP1. We detected two sequence alterations, each of which is likely to be pathogenic, since each segregates with the disease and is predicted to interfere with mRNA splicing. In contrast to some previously reported RLBP1 mutations, which yield a protein that may retain some residual activity, each NFRCD mutation is likely to give rise to a null allele. This difference may account for the severe phenotype in these families and exemplifies the molecular continuum that underlies clinically distinct but genetically related entities.

Authors
Eichers, ER; Green, JS; Stockton, DW; Jackman, CS; Whelan, J; McNamara, JA; Johnson, GJ; Lupski, JR; Katsanis, N
MLA Citation
Eichers, ER, Green, JS, Stockton, DW, Jackman, CS, Whelan, J, McNamara, JA, Johnson, GJ, Lupski, JR, and Katsanis, N. "Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1." Am J Hum Genet 70.4 (April 2002): 955-964.
PMID
11868161
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
70
Issue
4
Publish Date
2002
Start Page
955
End Page
964
DOI
10.1086/339688

Exploring the molecular basis of Bardet-Biedl syndrome.

Few autosomal recessive disorders display the degree of pleiotropism and genetic heterogeneity found in Bardet-Biedl syndrome (BBS), a genetic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, cognitive impairment and gonadal and renal dysgenesis. This relatively rare condition has been reported frequently, but we have only recently begun to appreciate the genetic complexities that give rise to this constellation of clinical findings. During the last 12 months, the first three of at least six BBS genes have been identified, providing us for the first time with the ability to formulate hypotheses regarding the molecular etiology of the disorder. Here we review the key elements of the phenotype and discuss the significance of the discovery of the first three BBS genes on the effort to identify the cellular causes of this syndrome.

Authors
Katsanis, N; Lupski, JR; Beales, PL
MLA Citation
Katsanis, N, Lupski, JR, and Beales, PL. "Exploring the molecular basis of Bardet-Biedl syndrome." Hum Mol Genet 10.20 (October 1, 2001): 2293-2299. (Review)
PMID
11673413
Source
pubmed
Published In
Human Molecular Genetics
Volume
10
Issue
20
Publish Date
2001
Start Page
2293
End Page
2299

Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders.

Authors
Katsanis, N; Ansley, SJ; Badano, JL; Eichers, ER; Lewis, RA; Hoskins, BE; Scambler, PJ; Davidson, WS; Beales, PL; Lupski, JR
MLA Citation
Katsanis, N, Ansley, SJ, Badano, JL, Eichers, ER, Lewis, RA, Hoskins, BE, Scambler, PJ, Davidson, WS, Beales, PL, and Lupski, JR. "Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder." Science 293.5538 (September 21, 2001): 2256-2259.
PMID
11567139
Source
pubmed
Published In
Science
Volume
293
Issue
5538
Publish Date
2001
Start Page
2256
End Page
2259
DOI
10.1126/science.1063525

An evaluation of the draft human genome sequence.

The completed draft version of the human genome, comprised of multiple short contigs encompassing 85% or more of euchromatin, was announced in June of 2000 (ref. 1). The detailed findings of the sequencing consortium were reported several months later. The draft sequence has provided insight into global characteristics, such as the total number of genes and a more accurate definition of gene families. Also of importance are genome positional details such as local genome architecture, regional gene density and the location of transcribed units that are critical for disease gene identification. We carried out a series of mapping and computational experiments using a nonredundant collection of 925 expressed sequence tags (ESTs) and sections of the public draft genome sequence that were available at different timepoints between April 2000 and April 2001. We found discrepancies in both the reported coverage of the human genome and the accuracy of mapping of genomic clones, suggesting some limitations of the draft genome sequence in providing accurate positional information and detailed characterization of chromosomal subregions.

Authors
Katsanis, N; Worley, KC; Lupski, JR
MLA Citation
Katsanis, N, Worley, KC, and Lupski, JR. "An evaluation of the draft human genome sequence." Nat Genet 29.1 (September 2001): 88-91.
PMID
11528399
Source
pubmed
Published In
Nature Genetics
Volume
29
Issue
1
Publish Date
2001
Start Page
88
End Page
91
DOI
10.1038/ng0901-88

Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1.

Fundus albipunctatus (FA; OMIM 136880) is a rare form of apparently stationary night blindness characterized by the presence of myriad symmetrical round white dots in the fundus with a greater concentration in the midperiphery. A distantly similar but distinct clinical entity, retinitis punctata albescens (RPA), is also characterized by aggregation of irregular white flecks but is progressive and evolves to generalized atrophy of the retina. We studied 4 consanguineous kindreds diagnosed with FA from Saudi Arabia. Given the substantial phenotypic variation and overlap between different flecked retinal dystrophies, we evaluated all known genes associated with such conditions by both genetic analysis and direct sequencing. In one kindred, KKESH-099, we identified a homozygous R150Q alteration in RLBP1, the gene encoding the cellular retinaldehyde binding protein, associated previously with both recessive retinitis pigmentosa (arRP) and RPA. Examination of several patients aged 3-20 years over a 9-year period presented no evidence for either RP or RPA. In contrast, clinical examination of individuals with the same mutation in their fourth and fifth decade revealed signs consistent with RPA. The data suggest that the R150Q mutation in RLBP1 may result in RPA with slow progression. More importantly, younger individuals diagnosed with the milder disorder FA thought to be stationary may evolve to a more devastating and progressive phenotype.

Authors
Katsanis, N; Shroyer, NF; Lewis, RA; Cavender, JC; Al-Rajhi, AA; Jabak, M; Lupski, JR
MLA Citation
Katsanis, N, Shroyer, NF, Lewis, RA, Cavender, JC, Al-Rajhi, AA, Jabak, M, and Lupski, JR. "Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1." Clin Genet 59.6 (June 2001): 424-429.
PMID
11453974
Source
pubmed
Published In
Clinical Genetics
Volume
59
Issue
6
Publish Date
2001
Start Page
424
End Page
429

The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes.

Duplication and deletion of the 1.4-Mb region in 17p12 that is delimited by two 24-kb low copy number repeats (CMT1A-REPs) represent frequent genomic rearrangements resulting in two common inherited peripheral neuropathies, Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP). CMT1A and HNPP exemplify a paradigm for genomic disorders wherein unique genome architectural features result in susceptibility to DNA rearrangements that cause disease. A gene within the 1.4-Mb region, PMP22, is responsible for these disorders through a gene-dosage effect in the heterozygous duplication or deletion. However, the genomic structure of the 1.4-Mb region, including other genes contained within the rearranged genomic segment, remains essentially uncharacterized. To delineate genomic structural features, investigate higher-order genomic architecture, and identify genes in this region, we constructed PAC and BAC contigs and determined the complete nucleotide sequence. This CMT1A/HNPP genomic segment contains 1,421,129 bp of DNA. A low copy number repeat (LCR) was identified, with one copy inside and two copies outside of the 1.4-Mb region. Comparison between physical and genetic maps revealed a striking difference in recombination rates between the sexes with a lower recombination frequency in males (0.67 cM/Mb) versus females (5.5 cM/Mb). Hypothetically, this low recombination frequency in males may enable a chromosomal misalignment at proximal and distal CMT1A-REPs and promote unequal crossing over, which occurs 10 times more frequently in male meiosis. In addition to three previously described genes, five new genes (TEKT3, HS3ST3B1, NPD008/CGI-148, CDRT1, and CDRT15) and 13 predicted genes were identified. Most of these predicted genes are expressed only in embryonic stages. Analyses of the genomic region adjacent to proximal CMT1A-REP indicated an evolutionary mechanism for the formation of proximal CMT1A-REP and the creation of novel genes by DNA rearrangement during primate speciation.

Authors
Inoue, K; Dewar, K; Katsanis, N; Reiter, LT; Lander, ES; Devon, KL; Wyman, DW; Lupski, JR; Birren, B
MLA Citation
Inoue, K, Dewar, K, Katsanis, N, Reiter, LT, Lander, ES, Devon, KL, Wyman, DW, Lupski, JR, and Birren, B. "The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes." Genome Res 11.6 (June 2001): 1018-1033.
PMID
11381029
Source
pubmed
Published In
Genome research
Volume
11
Issue
6
Publish Date
2001
Start Page
1018
End Page
1033
DOI
10.1101/gr.180401

New polymorphic short tandem repeats for PCR-based Charcot-Marie-Tooth disease type 1A duplication diagnosis.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) accounts for 70-90% of cases of CMT1 and is most frequently caused by the tandem duplication of a 1.4-Mb genomic fragment on chromosome 17p12. Molecular diagnosis of CMT1A has been based primarily on pulsed-field electrophoresis, fluorescence in situ hybridization, polymorphic allele dosage analysis, and quantitative PCR. We sought to improve the fidelity and applicability of PCR-based diagnosis by developing a panel of novel, highly polymorphic short tandem repeats (STRs) from within the CMT1A duplicated region. METHODS: We used a recently available genomic sequence to identify potentially polymorphic simple repeats. We then amplified these sequences in a multiethnic cohort of unaffected individuals and assessed the heterozygosity and number of alleles for each STR. Highly informative markers were then tested in a set of previously diagnosed CMT1A duplication patients, and the ability to identify the genomic duplication through the presence of three bands was assessed. RESULTS: We identified 34 polymorphic markers, 15 of which were suitable for CMT1A diagnosis on the basis of high heterozygosity in different ethnic groups, peak uniformity, and a large number of alleles. On the basis of the fluorescent dye and allele range of each marker, we developed two panels, each of which could be analyzed concurrently. Panel 1, which comprised 10 markers, detected 37 of 39 duplications, whereas panel 2, which comprised the remaining 5 markers, identified 21 of 39 duplications. Through the combination of both panels, we identified 39 of 39 duplications in previously diagnosed CMT1A patients. CONCLUSIONS: The newly developed 15-marker set has the capability of detecting > 99% of duplications and thus is a powerful and versatile diagnostic tool.

Authors
Badano, JL; Inoue, K; Katsanis, N; Lupski, JR
MLA Citation
Badano, JL, Inoue, K, Katsanis, N, and Lupski, JR. "New polymorphic short tandem repeats for PCR-based Charcot-Marie-Tooth disease type 1A duplication diagnosis." Clin Chem 47.5 (May 2001): 838-843.
PMID
11325886
Source
pubmed
Published In
Clinical chemistry
Volume
47
Issue
5
Publish Date
2001
Start Page
838
End Page
843

Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized primarily by obesity, polydactyly, retinal dystrophy, and renal disease. The significant genetic and clinical heterogeneity of this condition have substantially hindered efforts to positionally clone the numerous BBS genes, because the majority of available pedigrees are small and the disorder cannot be assigned to any of the six known BBS loci. Consequently, the delineation of critical BBS intervals, which would accelerate the discovery of the underlying genetic defect(s), becomes difficult, especially for loci with minor contributions to the syndrome. We have collected a cohort of 163 pedigrees from diverse ethnic backgrounds and have evaluated them for mutations in the recently discovered BBS6 gene (MKKS) on chromosome 20 and for potential assignment of the disorder to any of the other known BBS loci in the human genome. Using a combination of mutational and haplotype analysis, we describe the spectrum of BBS6 alterations that are likely to be pathogenic; propose substantially reduced critical intervals for BBS2, BBS3, and BBS5; and present evidence for the existence of at least one more BBS locus. Our data also suggest that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype.

Authors
Beales, PL; Katsanis, N; Lewis, RA; Ansley, SJ; Elcioglu, N; Raza, J; Woods, MO; Green, JS; Parfrey, PS; Davidson, WS; Lupski, JR
MLA Citation
Beales, PL, Katsanis, N, Lewis, RA, Ansley, SJ, Elcioglu, N, Raza, J, Woods, MO, Green, JS, Parfrey, PS, Davidson, WS, and Lupski, JR. "Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci." Am J Hum Genet 68.3 (March 2001): 606-616.
PMID
11179009
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
68
Issue
3
Publish Date
2001
Start Page
606
End Page
616
DOI
10.1086/318794

Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder predominantly characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism and renal malformations, with secondary features that include diabetes mellitus, endocrinological dysfunction and behavioural abnormalities. Despite an initial expectation of genetic homogeneity due to relative clinical uniformity, five BBS loci have been reported, with evidence for additional loci in the human genome; however, no genes for BBS have yet been identified. We performed a genome screen with BBS families from Newfoundland that were excluded from BBS1-5 and identified linkage with D20S189. Fine-mapping reduced the critical interval to 1.9 cM between D20S851 and D20S189, encompassing a chaperonin-like gene. Mutations in this gene were recently reported to be associated with McKusick-Kaufman syndrome (MKKS; ref. 8). Given both the mapping position and clinical similarities of these two syndromes, we screened MKKS and identified mutations in five Newfoundland and two European-American BBS pedigrees. Most are frameshift alleles that are likely to result in a non-functional protein. Our data suggest that a complete loss of function of the MKKS product, and thus an inability to fold a range of target proteins, is responsible for the clinical manifestations of BBS.

Authors
Katsanis, N; Beales, PL; Woods, MO; Lewis, RA; Green, JS; Parfrey, PS; Ansley, SJ; Davidson, WS; Lupski, JR
MLA Citation
Katsanis, N, Beales, PL, Woods, MO, Lewis, RA, Green, JS, Parfrey, PS, Ansley, SJ, Davidson, WS, and Lupski, JR. "Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome." Nat Genet 26.1 (September 2000): 67-70.
PMID
10973251
Source
pubmed
Published In
Nature Genetics
Volume
26
Issue
1
Publish Date
2000
Start Page
67
End Page
70
DOI
10.1038/79201

Identification of novel genes expressed during metanephric induction through single-cell library screening.

BACKGROUND: Development of the mature kidney is dependent on a series of inductive events between a portion of the epithelial bud at the distal end of the nephric duct and a neighboring domain of committed metanephric mesenchyme. Several genes have been identified to date that are critical in the inductive process. For example, the deletion of Bmp7 from the mouse genome results in dysgenesis or agenesis of the kidney. These findings suggest that Bmp7 controls the expression of genes important for nephrogenesis, but the identity of these genes has remained largely undetermined. METHODS: Single cells were isolated from mouse metanephric mesenchyme during the time of induction (between E11.0 and E11.5) and cDNA libraries constructed from induced and uninduced tissue. Subtractive hybridization was performed to isolate genes that were expressed during E11.5 but not E11.0. RESULTS: Using this approach, we identified eight previously known genes, three of which were known to be involved in metanephric induction, thus validating our approach, and nine novel genes. Eight of these genes were completely novel, whereas one was similar to a member of the yeast Anaphase Promoting Complex. CONCLUSIONS: Through subtractive hybridization of mouse E11.0 and E11.5 metanephric mesenchyme single-cell cDNA libraries, we have identified novel genes that are candidates for involvement in nephrogenesis through their up-regulation during the inductive process.

Authors
Abidari, JM; Gonzales, ET; Inoue, K; Lupski, JR; Karsenty, G; Katsanis, N
MLA Citation
Abidari, JM, Gonzales, ET, Inoue, K, Lupski, JR, Karsenty, G, and Katsanis, N. "Identification of novel genes expressed during metanephric induction through single-cell library screening." Kidney Int 57.6 (June 2000): 2221-2228.
PMID
10844592
Source
pubmed
Published In
Kidney international
Volume
57
Issue
6
Publish Date
2000
Start Page
2221
End Page
2228
DOI
10.1046/j.1523-1755.2000.00185.x

Isolation of a paralog of the Doyne honeycomb retinal dystrophy gene from the multiple retinopathy critical region on 11q13.

A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement, and determination of cell fate during development. The gene for one such protein, S1-5, was identified from a subtractively enriched cDNA library from a patient with Werner syndrome and was shown to be preferentially expressed in senescent and quiescent fibroblasts. We have cloned and characterized, in human and mouse, a novel gene that shows significant homology to the gene for S1-5. We have determined that the encoded protein contains four EGF domains and six calcium-binding EGF domains. On the basis of its homology to known proteins, we have designated this gene EFEMP2 (Egf-containing fibulin-like extracellular matrix protein 2) and the gene for the S1-5 protein EFEMP1. Like EFEMP1, this novel gene is expressed in a wide range of adult and fetal tissues. In contrast to EFEMP1, however, EFEMP2 is not significantly overexpressed in senescent or quiescent fibroblasts, suggesting a diversity of function within this new EGF-like domain subfamily. We have mapped EFEMP2 to 11q13, in an area where several retinopathies have been genetically linked. Given that mutations in EFEMP1 have been recently described in patients with Doyne honeycomb retinal dystrophy, EFEMP2 becomes a good candidate for such disorders.

Authors
Katsanis, N; Venable, S; Smith, JR; Lupski, JR
MLA Citation
Katsanis, N, Venable, S, Smith, JR, and Lupski, JR. "Isolation of a paralog of the Doyne honeycomb retinal dystrophy gene from the multiple retinopathy critical region on 11q13." Hum Genet 106.1 (January 2000): 66-72.
PMID
10982184
Source
pubmed
Published In
Human Genetics
Volume
106
Issue
1
Publish Date
2000
Start Page
66
End Page
72

Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous recessive disease characterized primarily by atypical retinitis pigmentosa, obesity, polydactyly, hypogenitalism, and mental retardation. Despite the presence of at least five loci in the human genome, on chromosomes 2q, 3p, 11q, 15q and 16q, as many as 50% of the mutations appear to map to the BBS1 locus on 11q13. The recessive mode of inheritance and the genetic heterogeneity of the syndrome, as well as the inability to distinguish between different genetic loci by phenotypic analyses, have hindered efforts to delineate the 11q13 region as a first step toward cloning the mutated gene. To circumvent these difficulties, we collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis, using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in two consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. The identification of multiple recombinants at the same position forms the basis for physical mapping efforts, coupled with mutation analysis of candidate genes, to identify the gene for BBS1.

Authors
Katsanis, N; Lewis, RA; Stockton, DW; Mai, PM; Baird, L; Beales, PL; Leppert, M; Lupski, JR
MLA Citation
Katsanis, N, Lewis, RA, Stockton, DW, Mai, PM, Baird, L, Beales, PL, Leppert, M, and Lupski, JR. "Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees." Am J Hum Genet 65.6 (December 1999): 1672-1679.
PMID
10577921
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
65
Issue
6
Publish Date
1999
Start Page
1672
End Page
1679
DOI
10.1086/302684

High-resolution comparative physical mapping of mouse chromosome 10 in the region of homology with human chromosome 21.

Comparative mapping of human and mouse chromosomes can be used to predict locations of homologous loci between the species, provides the substrate to examine the process of chromosomal evolution, and facilitates the continuing development of mouse genetic models for human disorders. A YAC contig of the region of mouse Chromosome (Chr) 10 (MMU10) that demonstrates conserved linkage with the distal portion of human Chr 21 (HSA21) has been constructed. The contig contains all known genes mapped in both species, defines the proximal region of homology between MMU10 and HSA22, and contains the evolutionary junction between HSA21 and HSA22 on MMU10. It consists of 23 YACs and 2 PACs, and covers 3.2 Mb of MMU10. The average marker density for this region is 1 marker/69 kb. Nine of 22 expressed sequences are mapped here for the first time in mouse, and two are newly characterized expressed sequences. The contig also contains 12 simple sequence repeats (SSRs) and 16 YAC and PAC endclone markers. YAC fragmentation analysis was used to create a physical map for the proximal 2.2 Mb of the contig. Cloning of the corresponding region of HSA21 has proven difficult, and the mouse contig includes segments absent from previously described sequence ready maps of HSA21.

Authors
Cole, SE; Wiltshire, T; Rue, EE; Morrow, D; Hieter, P; Brahe, C; Fisher, EM; Katsanis, N; Reeves, RH
MLA Citation
Cole, SE, Wiltshire, T, Rue, EE, Morrow, D, Hieter, P, Brahe, C, Fisher, EM, Katsanis, N, and Reeves, RH. "High-resolution comparative physical mapping of mouse chromosome 10 in the region of homology with human chromosome 21." Mamm Genome 10.3 (March 1999): 229-234.
PMID
10051316
Source
pubmed
Published In
Mammalian Genome
Volume
10
Issue
3
Publish Date
1999
Start Page
229
End Page
234

Report of the Sixth International Workshop on Human Chromosome 11 Mapping 1998. Nice, France, May 2-5, 1998.

Authors
Gaudray, P; Carle, GF; Gerhard, DS; Gessler, M; Mannens, MM; Athanasiou, M; Bliek, J; Calender, A; Debelenko, LV; Devignes, M; Evans, GA; Favier, R; Forbes, S; Gaudray, G; Gawin, B; Gordon, M; Grimmond, S; Grossfeld, P; Harris, J; Hattori, M; Hosoda, F; Hummerich, H; James, M; Kalla, J; Katsanis, N
MLA Citation
Gaudray, P, Carle, GF, Gerhard, DS, Gessler, M, Mannens, MM, Athanasiou, M, Bliek, J, Calender, A, Debelenko, LV, Devignes, M, Evans, GA, Favier, R, Forbes, S, Gaudray, G, Gawin, B, Gordon, M, Grimmond, S, Grossfeld, P, Harris, J, Hattori, M, Hosoda, F, Hummerich, H, James, M, Kalla, J, and Katsanis, N. "Report of the Sixth International Workshop on Human Chromosome 11 Mapping 1998. Nice, France, May 2-5, 1998." Cytogenet Cell Genet 86.3-4 (1999): 167-186.
PMID
10575203
Source
pubmed
Published In
Cytogenetics and cell genetics
Volume
86
Issue
3-4
Publish Date
1999
Start Page
167
End Page
186

Sixth International Workshop on Human Chromosome 11 Mapping, Nice, Paris, 2-5 May, 1998

Authors
Gaudray, P; Carle, GF; Gerhard, DS; Gessler, M; Mannens, MM; Athanasiou, M; Bliek, J; Calender, A; Debelenko, LV; Devignes, M-D; Evans, GA; Favier, R; Forbes, S; Gaudray, G; Gawin, B; Gordon, M; Grimmond, S; Grossfeld, P; Harris, J; Hattori, M; Hosoda, F; Hummerich, H; James, M; Kalla, J; Katsanis, N; Little, P; Mattina, T; Negrini, M; Ohki, M; Lawrence, SO; Parente, F; Quincey, D; Raynaud, S; Reid, L; Rethy, LA; Schuuring, E; Sellar, G; Stilgenbauer, S; Talbot, C; Taschner, P; Thangarajah, T et al.
MLA Citation
Gaudray, P, Carle, GF, Gerhard, DS, Gessler, M, Mannens, MM, Athanasiou, M, Bliek, J, Calender, A, Debelenko, LV, Devignes, M-D, Evans, GA, Favier, R, Forbes, S, Gaudray, G, Gawin, B, Gordon, M, Grimmond, S, Grossfeld, P, Harris, J, Hattori, M, Hosoda, F, Hummerich, H, James, M, Kalla, J, Katsanis, N, Little, P, Mattina, T, Negrini, M, Ohki, M, Lawrence, SO, Parente, F, Quincey, D, Raynaud, S, Reid, L, Rethy, LA, Schuuring, E, Sellar, G, Stilgenbauer, S, Talbot, C, Taschner, P, and Thangarajah, T et al. "Sixth International Workshop on Human Chromosome 11 Mapping, Nice, Paris, 2-5 May, 1998." Cytogenetics and Cell Genetics 86.3-4 (1999): 168-186.
Source
scival
Published In
Cytogenetics and Cell Genetics
Volume
86
Issue
3-4
Publish Date
1999
Start Page
168
End Page
186

Identification, expression, and chromosomal localization of ubiquitin conjugating enzyme 7 (UBE2G2), a human homologue of the Saccharomyces cerevisiae ubc7 gene.

Protein degradation is an essential mechanism for the maintenance of cellular homeostasis, in which excess or aberrant proteins are eliminated from the cell. In eukaryotes, conjugation of target proteins to ubiquitin is an essential step in the proteasome-dependent degradation process and is mediated by a family of ubiquitin conjugating enzymes (UBC). Several of these have been identified in a variety of organisms. Here we report the identification of UBE2G2, a human homologue of the yeast Ubc7 gene. We describe a 2.9-kb cDNA sequence encoding a 165-amino-acid protein that shares significant similarity with other members of the UBC family. We have found UBE2G2 to be ubiquitously expressed, with high levels of expression seen in adult muscle, and have detected two transcripts of 2.9 and 7.0 kb in all tissues. In addition, we have mapped UBC7 to human chromosome 21q22.3 close to 21qtel.

Authors
Katsanis, N; Fisher, EM
MLA Citation
Katsanis, N, and Fisher, EM. "Identification, expression, and chromosomal localization of ubiquitin conjugating enzyme 7 (UBE2G2), a human homologue of the Saccharomyces cerevisiae ubc7 gene." Genomics 51.1 (July 1, 1998): 128-131.
PMID
9693041
Source
pubmed
Published In
Genomics
Volume
51
Issue
1
Publish Date
1998
Start Page
128
End Page
131
DOI
10.1006/geno.1998.5263

The immunophilin FKBP4 (FKBP52/FKBP59) maps to the distal short arm of human chromosome 12.

Authors
Bermingham, NA; Rauf, S; Katsanis, N; Martin, JE; Hunter, AJ; Fisher, EM
MLA Citation
Bermingham, NA, Rauf, S, Katsanis, N, Martin, JE, Hunter, AJ, and Fisher, EM. "The immunophilin FKBP4 (FKBP52/FKBP59) maps to the distal short arm of human chromosome 12." Mamm Genome 9.3 (March 1998): 268-.
PMID
9501323
Source
pubmed
Published In
Mammalian Genome
Volume
9
Issue
3
Publish Date
1998
Start Page
268

High resolution physical mapping and identification of transcribed sequences in the Down syndrome region-2.

The identification and mapping of genes within the Down syndrome region is an important step toward a complete understanding of the pathogenesis of this disorder. The objective of the present work is to identify and map genes within the Down syndrome region-2. Chromosome 21 cosmid clones corresponding to "cosmid pockets" 121-124 have been first used as a starting material for generation of a single high resolution integrated cosmid/PAC contig with full EcoRI/SmaI restriction map. The integrated contig has been further anchored to genetic and physical maps through the positioning of 6 markers in the following order: ACTL5-D21S3-684G2T7-D21S71-D21S343-D21S 268. The entire contig covers 342 kb of the Down syndrome region-2 of chromosome 21. Subsequently, we have isolated, identified, and mapped four novel cDNAs which we have named N143, N144, CHD/333, and 90/3H1 and a potentially transcribed genomic sequence (E05133T7). Additionally, we have accurately located a previously described gene, the WRB gene, between the markers ACTL5-D21S268 within this Down Syndrome Region-2.

Authors
Vidal-Taboada, JM; Bergoñón, S; Sánchez, M; López-Acedo, C; Groet, J; Nizetic, D; Egeo, A; Scartezzini, P; Katsanis, N; Fisher, EM; Delabar, JM; Oliva, R
MLA Citation
Vidal-Taboada, JM, Bergoñón, S, Sánchez, M, López-Acedo, C, Groet, J, Nizetic, D, Egeo, A, Scartezzini, P, Katsanis, N, Fisher, EM, Delabar, JM, and Oliva, R. "High resolution physical mapping and identification of transcribed sequences in the Down syndrome region-2." Biochem Biophys Res Commun 243.2 (February 13, 1998): 572-578.
PMID
9480850
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
243
Issue
2
Publish Date
1998
Start Page
572
End Page
578
DOI
10.1006/bbrc.1998.8141

Localisation of receptor interacting protein 140 (RIP140) within 100 kb of D21S13 on 21q11, a gene-poor region of the human genome.

Human chromosome 21 is the smallest and one of the most intensively studied autosomes. The generation of high quality genetic and physical maps for the long arm has enabled the research community to accelerate gene discovery and the identification of disease loci on the chromosome. However, the emerging pattern from large-scale transcriptional mapping from many groups suggests that the majority of the 600-1000 genes predicted to reside on the chromosome are clustered in two distinct regions of the long arm, on distal 21q22.1 and 21q22.3. Here, we report the mapping of the gene for receptor interacting protein 140 (RIP140) on 21q11 by means of YACs, PACs and hybrid cell lines. We have placed RIP140 within 100 kb of D21S13, in a region of the chromosome where only one other gene has been described to date. The association of the RIP140 protein with the superfamily of nuclear receptors may be of significance in studies of trisomy 21 (Down syndrome) and Alzheimers disease, since a modifier locus has been speculated to reside on 21q11.

Authors
Katsanis, N; Ives, JH; Groet, J; Nizetic, D; Fisher, EM
MLA Citation
Katsanis, N, Ives, JH, Groet, J, Nizetic, D, and Fisher, EM. "Localisation of receptor interacting protein 140 (RIP140) within 100 kb of D21S13 on 21q11, a gene-poor region of the human genome." Hum Genet 102.2 (February 1998): 221-223.
PMID
9521594
Source
pubmed
Published In
Human Genetics
Volume
102
Issue
2
Publish Date
1998
Start Page
221
End Page
223

A novel C-terminal binding protein (CTBP2) is closely related to CTBP1, an adenovirus E1A-binding protein, and maps to human chromosome 21q21.3.

A region of the C-terminus of adenovirus type 2/5 E1A protein has been associated with negative modulation of tumorigenicity, as well as the extent of oncogenic transformation. In contrast with the N-terminus of the E1A protein, which has been extensively characterized and shown to associate with a number of cellular proteins, the function of the C-terminus is poorly understood. To date, a single 48-kDa protein, CTBP1, has been shown to associate with this region. Here we report the identification and sequence of a novel gene in human (CTBP2) and mouse (Ctbp2), both highly related to CTBP1 and thus also likely to bind to the E1A protein. We found that CTBP2 is expressed in all tissues tested, with a higher level of expression in the heart, skeletal muscle, and pancreas. We mapped CTBP1 and CTBP2 to human chromosomes 4p16 and 21q21.3, respectively.

Authors
Katsanis, N; Fisher, EM
MLA Citation
Katsanis, N, and Fisher, EM. "A novel C-terminal binding protein (CTBP2) is closely related to CTBP1, an adenovirus E1A-binding protein, and maps to human chromosome 21q21.3." Genomics 47.2 (January 15, 1998): 294-299.
PMID
9479502
Source
pubmed
Published In
Genomics
Volume
47
Issue
2
Publish Date
1998
Start Page
294
End Page
299
DOI
10.1006/geno.1997.5115

Mapping of a novel SH3 domain protein and two proteins of unknown function to human chromosome 21.

Down syndrome, caused by trisomy of human chromosome 21 (HSA21), is the most common autosomal form of mental retardation. To understand the aetiology of the syndrome we need to identify the genes involved. We have utilised the information generated by the various EST sequencing projects to enrich the transcription map of chromosome 21. Here we report the mapping of SH3P17 to 21q22.1 and the localisation of two genes previously mapped to HSA21 by Nagase and colleagues, KIAA0136 and KIAA0179 to 21q22.2 and 21q22.3, respectively. SH3P17 has unknown function but contains four SH3 domains. KIAA0136 shows no homology to a yeast open reading frame. Further investigation of these three genes will add to our functional understanding of HSA21.

Authors
Katsanis, N; Beck, JA; Fisher, EM
MLA Citation
Katsanis, N, Beck, JA, and Fisher, EM. "Mapping of a novel SH3 domain protein and two proteins of unknown function to human chromosome 21." Hum Genet 100.3-4 (September 1997): 477-480.
PMID
9272176
Source
pubmed
Published In
Human Genetics
Volume
100
Issue
3-4
Publish Date
1997
Start Page
477
End Page
480

Identification and mapping of a novel human gene, HRMT1L1, homologous to the rat protein arginine N-methyltransferase 1 (PRMT1) gene.

Authors
Katsanis, N; Yaspo, ML; Fisher, EM
MLA Citation
Katsanis, N, Yaspo, ML, and Fisher, EM. "Identification and mapping of a novel human gene, HRMT1L1, homologous to the rat protein arginine N-methyltransferase 1 (PRMT1) gene." Mamm Genome 8.7 (July 1997): 526-529.
PMID
9196002
Source
pubmed
Published In
Mammalian Genome
Volume
8
Issue
7
Publish Date
1997
Start Page
526
End Page
529

The gene encoding the p60 subunit of chromatin assembly factor I (CAF1P60) maps to human chromosome 21q22.2, a region associated with some of the major features of Down syndrome.

Trisomy 21 is the most common aneuploidy in humans with a frequency of 1 in 700 live births and is by far the most common defined cause of mental retardation. To analyse which of the chromosome 21 genes is overexpressed early in development-giving rise to the Down syndrome phenotype-and to provide candidate genes for other HSA21 disease loci, we need a transcription map of the chromosome. Therefore, to enrich the gene map of human chromosome 21 we have undertaken a systematic approach to fine mapping and characterising expressed sequences generated by the various cDNA sequencing projects. In this report we show the localisation of the CAF1P60 gene to human chromosome 21 and its fine mapping to 21q22.2 between D21S333 and D21S334. This mapping position places CAF1P60 in a region of HSA21 which is strongly associated with the major features of Down syndrome. The function of this gene product may have important implications for the phenotype that arises from trisomy 21.

Authors
Katsanis, N; Fisher, EM
MLA Citation
Katsanis, N, and Fisher, EM. "The gene encoding the p60 subunit of chromatin assembly factor I (CAF1P60) maps to human chromosome 21q22.2, a region associated with some of the major features of Down syndrome." Hum Genet 98.4 (October 1996): 497-499.
PMID
8792829
Source
pubmed
Published In
Human Genetics
Volume
98
Issue
4
Publish Date
1996
Start Page
497
End Page
499

Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci.

The human genome contains a group of gene families whose members map within the same regions of chromosomes 1, 6, and 9. The number of gene families involved and their pronounced clustering to the same areas of the genome indicate that their mapping relationship is nonrandom. By combining mapping data and sequence information for the gene families, we have determined that these sequences are part of a large region that spans several megabases. This region is present in three copies: on the long arm of human chromosome 1, the short arm of chromosome 6, and the long arm of chromosome 9. We have characterized the phylogenesis of two of the gene families involved and propose an evolutionary route for the creation of the three regions. Our analysis led us to predict and demonstrate the presence of two loci, a PBX locus on chromosome 6 and a NOTCH locus on chromosome 1. The discovery of this triplicated region increases our understanding of the evolution of the human genome and may have considerable practical implications for gene mapping prediction and novel approaches to isolating new gene family members and uncloned disease loci.

Authors
Katsanis, N; Fitzgibbon, J; Fisher, EM
MLA Citation
Katsanis, N, Fitzgibbon, J, and Fisher, EM. "Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci." Genomics 35.1 (July 1, 1996): 101-108.
PMID
8661110
Source
pubmed
Published In
Genomics
Volume
35
Issue
1
Publish Date
1996
Start Page
101
End Page
108
DOI
10.1006/geno.1996.0328

Human guanylate kinase (GUK1): cDNA sequence, expression and chromosomal localisation.

Guanylate kinase (GK) catalyses the conversion of GMP to GTP as part of the cGMP cycle. In mammalian phototransduction, this cycle is essential for the regeneration of cGMP following its hydrolysis by phosphodiesterase. Mutations in different parts of this signalling cascade lead to retinal degeneration in humans. Protein studies have localized a locus for GK to a region of human chromosome 1 that also contains an autosomal recessive form of retinitis pigmentosa (RP12) and Usher's type 11a (USH2A). We report the sequence of this human GK (GUK1) and a further refinement of its localization to 1q32-41, placing it in the same interval as USH2A.

Authors
Fitzgibbon, J; Katsanis, N; Wells, D; Delhanty, J; Vallins, W; Hunt, DM
MLA Citation
Fitzgibbon, J, Katsanis, N, Wells, D, Delhanty, J, Vallins, W, and Hunt, DM. "Human guanylate kinase (GUK1): cDNA sequence, expression and chromosomal localisation." FEBS Lett 385.3 (May 6, 1996): 185-188.
PMID
8647247
Source
pubmed
Published In
FEBS Letters
Volume
385
Issue
3
Publish Date
1996
Start Page
185
End Page
188

An improved protocol for the analysis of SOD1 gene mutations, and a new mutation in exon 4.

Authors
Yulug, IG; Katsanis, N; de Belleroche, J; Collinge, J; Fisher, EM
MLA Citation
Yulug, IG, Katsanis, N, de Belleroche, J, Collinge, J, and Fisher, EM. "An improved protocol for the analysis of SOD1 gene mutations, and a new mutation in exon 4." Hum Mol Genet 4.6 (June 1995): 1101-1104.
PMID
7655468
Source
pubmed
Published In
Human Molecular Genetics
Volume
4
Issue
6
Publish Date
1995
Start Page
1101
End Page
1104

Erratum: An improved protocol for the analysis of SOD1 gene mutations, and a new mutation in exon 4 (Human Molecular Genetics 4 (1101-1104))

Authors
Yulug, IG; Katsanis, N; Belleroche, JD; Collinge, J; Fisher, EMC
MLA Citation
Yulug, IG, Katsanis, N, Belleroche, JD, Collinge, J, and Fisher, EMC. "Erratum: An improved protocol for the analysis of SOD1 gene mutations, and a new mutation in exon 4 (Human Molecular Genetics 4 (1101-1104))." Human Molecular Genetics 4.8 (1995): 1474--.
Source
scival
Published In
Human Molecular Genetics
Volume
4
Issue
8
Publish Date
1995
Start Page
1474-

An improved protocol for the analysis of SODI gene mutations, and a new mutation in exon 4

The publishers wish to apologise for the omission of Figure 2 from the above paper. The missing figure is shown below. © 1995 Oxford University Press.

Authors
Yulug, IG; Katsanis, N; Belleroche, JD; Collinge, J; Fisher, EMC
MLA Citation
Yulug, IG, Katsanis, N, Belleroche, JD, Collinge, J, and Fisher, EMC. "An improved protocol for the analysis of SODI gene mutations, and a new mutation in exon 4." Human Molecular Genetics 4.8 (1995): 1474--.
Source
scival
Published In
Human Molecular Genetics
Volume
4
Issue
8
Publish Date
1995
Start Page
1474-
DOI
10.1093/hmg/4.8.1474
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