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Davis, Erica Ellen

Overview:

Two key questions thematically underscore my research in the Center for Human Disease Modeling at Duke University: First of all, how can variation at the DNA level be functionally interpreted beyond the resolution of genetics arguments alone? Secondly, once empowered with functional information about genetic variants, how can pathogenic alleles be mapped back to disease phenotypes? Using the ciliary disease module as a model system of investigation, we are using multidisciplinary tactics to address these questions and continue to harness these approaches toward the further dissection of the architecture of human genetic disease. Moreover, we have applied the in vivo tools and lessons learned from ciliary phenotypes affecting the renal, craniofacial, and central nervous systems to interrogate rare pediatric disorders characterized by these phenotypic hallmarks.


Positions:

Associate Professor of Pediatrics

Pediatrics, Neonatology
School of Medicine

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Associate Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2005

Ph.D. — University of Liege (Belgium)

News:

Grants:

Transcriptomic, therapeutic and genetic investigations of sickle cell nephropathy

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
August 18, 2016
End Date
July 31, 2019

RPB: 2014 Nelson Trust Award

Administered By
Ophthalmology
AwardedBy
Research To Prevent Blindness, Inc.
Role
Collaborator
Start Date
July 01, 2014
End Date
June 30, 2019

Functional and Phenotypic Characterization of a New FSGS Gene

Administered By
Pediatrics, Nephrology
AwardedBy
National Institutes of Health
Role
Co Investigator
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
Co-Principal Investigator
Start Date
August 01, 2005
End Date
February 28, 2019

The Genetic Architecture of Neurodegenerative Disorders

Administered By
Institutes and Centers
AwardedBy
Rescindo Therapeutics Inc
Role
Principal Investigator
Start Date
December 01, 2016
End Date
November 30, 2017

Epigenetic Control of Intestinal Inflammation

Administered By
Cell Biology
AwardedBy
Kenneth Rainin Foundation
Role
Co Investigator
Start Date
October 01, 2016
End Date
September 30, 2017

Genetic and Molecular Analysis of Congenital Heart Disease

Administered By
Institutes and Centers
AwardedBy
University of Chicago
Role
Co 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
Co Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Genetics of Congenital Obstructive Uropathy

Administered By
Institutes and Centers
AwardedBy
Columbia University
Role
Principal Investigator
Start Date
July 01, 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
Co Investigator
Start Date
September 18, 2012
End Date
June 30, 2017

Duke Training Grant in Nephrology

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
September 20, 1995
End Date
June 30, 2017

Modifiers of Retinal Phenotypes in Ciliopathies

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2011
End Date
February 28, 2017

Genomic Architecture of Common Disease in Diverse Populations

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

Epigenetic control of intestinal inflammation

Administered By
Cell Biology
AwardedBy
Kenneth Rainin Foundation
Role
Co Investigator
Start Date
October 01, 2015
End Date
September 30, 2016
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Publications:

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.

Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

Authors
Ta-Shma, A; Khan, TN; Vivante, A; Willer, JR; Matak, P; Jalas, C; Pode-Shakked, B; Salem, Y; Anikster, Y; Hildebrandt, F; Katsanis, N; Elpeleg, O; Davis, EE
MLA Citation
Ta-Shma, A, Khan, TN, Vivante, A, Willer, JR, Matak, P, Jalas, C, Pode-Shakked, B, Salem, Y, Anikster, Y, Hildebrandt, F, Katsanis, N, Elpeleg, O, and Davis, EE. "Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome." American journal of human genetics 100.4 (April 2017): 666-675.
PMID
28318500
Source
epmc
Published In
The American Journal of Human Genetics
Volume
100
Issue
4
Publish Date
2017
Start Page
666
End Page
675
DOI
10.1016/j.ajhg.2017.02.007

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 49.2 (February 2017): 238-248.
PMID
28067909
Source
epmc
Published In
Nature Genetics
Volume
49
Issue
2
Publish Date
2017
Start Page
238
End Page
248
DOI
10.1038/ng.3743

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

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

A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay.

Genetic studies grounded on monogenic paradigms have accelerated both gene discovery and molecular diagnosis. At the same time, complex genomic rearrangements are also appreciated as potent drivers of disease pathology. Here, we report two male siblings with a dysmorphic face, ambiguous genitalia, intellectual disability, and speech delay. Through quad-based whole-exome sequencing and concomitant molecular cytogenetic testing, we identified two copy-number variants (CNVs) in both affected individuals likely arising from a balanced translocation: a 13.5-Mb duplication on Chromosome 16 (16q23.1 → 16qter) and a 7.7-Mb deletion on Chromosome 5 (5p15.31 → 5pter), as well as a hemizygous missense variant in CXorf36 (also known as DIA1R). The 5p terminal deletion has been associated previously with speech delay, whereas craniofacial dysmorphia and genital/urinary anomalies have been reported in patients with a terminal duplication of 16q. However, dosage changes in either genomic region alone could not account for the overall clinical presentation in our family; functional testing of CXorf36 in zebrafish did not induce defects in neurogenesis or the craniofacial skeleton. Notably, literature and database analysis revealed a similar dosage disruption in two siblings with extensive phenotypic overlap with our patients. Taken together, our data suggest that dosage perturbation of genes within the two chromosomal regions likely drives the syndromic manifestations of our patients and highlight how multiple genetic lesions can contribute to complex clinical pathologies.

Authors
Ozantürk, A; Davis, EE; Sabo, A; Weiss, MM; Muzny, D; Dugan-Perez, S; Sistermans, EA; Gibbs, RA; Özgül, KR; Yalnızoglu, D; Serdaroglu, E; Dursun, A; Katsanis, N
MLA Citation
Ozantürk, A, Davis, EE, Sabo, A, Weiss, MM, Muzny, D, Dugan-Perez, S, Sistermans, EA, Gibbs, RA, Özgül, KR, Yalnızoglu, D, Serdaroglu, E, Dursun, A, and Katsanis, N. "A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay." Cold Spring Harbor molecular case studies 2.2 (March 2016): a000703-.
PMID
27148584
Source
epmc
Published In
Cold Spring Harbor molecular case studies
Volume
2
Issue
2
Publish Date
2016
Start Page
a000703
DOI
10.1101/mcs.a000703

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

Ectopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy

Authors
Xu, X; Ectors, F; Davis, EE; Pirottin, D; Cheng, H; Farnir, F; Hadfield, T; Cockett, N; Charlier, C; Georges, M; Takeda, H
MLA Citation
Xu, X, Ectors, F, Davis, EE, Pirottin, D, Cheng, H, Farnir, F, Hadfield, T, Cockett, N, Charlier, C, Georges, M, and Takeda, H. "Ectopic Expression of Retrotransposon-Derived PEG11/RTL1 Contributes to the Callipyge Muscular Hypertrophy." Ed. A Asakura. PLOS ONE 10.10 (October 16, 2015): e0140594-e0140594.
Source
crossref
Published In
PloS one
Volume
10
Issue
10
Publish Date
2015
Start Page
e0140594
End Page
e0140594
DOI
10.1371/journal.pone.0140594

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

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. "Correction: In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress." PLoS genetics 11.9 (September 17, 2015): e1005459-.
PMID
26379250
Source
epmc
Published In
PLoS genetics
Volume
11
Issue
9
Publish Date
2015
Start Page
e1005459
DOI
10.1371/journal.pgen.1005459

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

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

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 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

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

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

Evidence for a Dominant Negative Effect Conferred By the APOL1 G2 Sickle Cell Nephropathy Risk Allele in an in Vivo Model

Authors
Anderson, BR; Davis, EE; Telen, MJ; Ashley-Koch, AE
MLA Citation
Anderson, BR, Davis, EE, Telen, MJ, and Ashley-Koch, AE. "Evidence for a Dominant Negative Effect Conferred By the APOL1 G2 Sickle Cell Nephropathy Risk Allele in an in Vivo Model." December 6, 2014.
Source
wos-lite
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

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

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

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

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

COMBINED D-2 AND L-2 HYDROXYGLUTARIC ACIDURIA PRESENTING WITH FACIAL DYSMORPHISM AND MULTIPLE MALFORMATIONS

Authors
Prasun, P; Young, S; Davis, EE; Jiang, Y-H; Struys, E; Salomons, G; McDonald, M
MLA Citation
Prasun, P, Young, S, Davis, EE, Jiang, Y-H, Struys, E, Salomons, G, and McDonald, M. "COMBINED D-2 AND L-2 HYDROXYGLUTARIC ACIDURIA PRESENTING WITH FACIAL DYSMORPHISM AND MULTIPLE MALFORMATIONS." March 2014.
Source
wos-lite
Published In
Molecular Genetics and Metabolism
Volume
111
Issue
3
Publish Date
2014
Start Page
242
End Page
242

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

In Vivo Modeling Of Genetic Mechanisms Associated With Sickle Cell Disease Nephropathy

Authors
Anderson, BR; Davis, EE; Telen, MJ; Ashley-Koch, AE
MLA Citation
Anderson, BR, Davis, EE, Telen, MJ, and Ashley-Koch, AE. "In Vivo Modeling Of Genetic Mechanisms Associated With Sickle Cell Disease Nephropathy." November 15, 2013.
Source
wos-lite
Published In
Blood
Volume
122
Issue
21
Publish Date
2013

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

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

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

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

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

Delta-Like 1 Homolog (Dlk1): A Marker for Rhabdomyosarcomas Implicated in Skeletal Muscle Regeneration

Dlk1, a member of the Epidermal Growth Factor family, is expressed in multiple tissues during development, and has been detected in carcinomas and neuroendocrine tumors. Dlk1 is paternally expressed and belongs to a group of imprinted genes associated with rhabdomyosarcomas but not with other primitive childhood tumors to date. Here, we investigate the possible roles of Dlk1 in skeletal muscle tumor formation. We analyzed tumors of different mesenchymal origin for expression of Dlk1 and various myogenic markers and found that Dlk1 was present consistently in myogenic tumors. The coincident observation of Dlk1 with a highly proliferative state in myogenic tumors led us to subsequently investigate the involvement of Dlk1 in the control of the adult myogenic programme. We performed an injury study in Dlk1 transgenic mice, ectopically expressing ovine Dlk1 (membrane bound C2 variant) under control of the myosin light chain promotor, and detected an early, enhanced formation of myotubes in Dlk1 transgenic mice. We then stably transfected the mouse myoblast cell line, C2C12, with full-length Dlk1 (soluble A variant) and detected an inhibition of myotube formation, which could be reversed by adding Dlk1 antibody to the culture supernatant. These results suggest that Dlk1 is involved in controlling the myogenic programme and that the various splice forms may exert different effects. Interestingly, both in the Dlk1 transgenic mice and the DLK1-C2C12 cells, we detected reduced myostatin expression, suggesting that the effect of Dlk1 on the myogenic programme might involve the myostatin signaling pathway. In support of a relationship between Dlk1 and myostatin we detected reciprocal expression of these two transcripts during different cell cycle stages of human myoblasts. Together our results suggest that Dlk1 is a candidate marker for skeletal muscle tumors and might be involved directly in skeletal muscle tumor formation through a modulatory effect on the myogenic programme. © 2013 Jørgensen et al.

Authors
Jørgensen, LH; Sellathurai, J; Davis, EE; Thedchanamoorthy, T; Al-Bader, RWA; Jensen, CH; Schrøder, HD
MLA Citation
Jørgensen, LH, Sellathurai, J, Davis, EE, Thedchanamoorthy, T, Al-Bader, RWA, Jensen, CH, and Schrøder, HD. "Delta-Like 1 Homolog (Dlk1): A Marker for Rhabdomyosarcomas Implicated in Skeletal Muscle Regeneration." PLoS ONE 8.4 (2013).
PMID
23577150
Source
scival
Published In
PloS one
Volume
8
Issue
4
Publish Date
2013
DOI
10.1371/journal.pone.0060692

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Elucidation of the effectors responsible for the callipyge phenotype and the trans-inhibitors contributing to polar overdominance

Authors
Davis, E
MLA Citation
Davis, E. "Elucidation of the effectors responsible for the callipyge phenotype and the trans-inhibitors contributing to polar overdominance." Annales de Medecine Veterinaire 151.SPEC. ISS. (2007): 1-2.
Source
scival
Published In
Annales de medecine veterinaire
Volume
151
Issue
SPEC. ISS.
Publish Date
2007
Start Page
1
End Page
2

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

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

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

Public access failure at PubMed [1]

Authors
Stebbins, M; Davis, E; Royland, L; White, G
MLA Citation
Stebbins, M, Davis, E, Royland, L, and White, G. "Public access failure at PubMed [1]." Science 313.5783 (2006): 43--.
PMID
16825550
Source
scival
Published In
Science
Volume
313
Issue
5783
Publish Date
2006
Start Page
43-

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 callipyge phenomenon: Cis effects, trans effects, and polar overdominance

The callipyge phenotype is a postnatal muscular hypertrophy characterized in sheep. Callipyge follows an unusual, non-Mendelian mode of inheritance, referred to as "polar overdominance" in which only heterozygous animals having received the mutation from their sire display the phenotype. The callipyge (CLPG) locus maps to the DLK1-GTL2 imprinted domain and the causal mutation is a single nucleotide polymorphism (SNP) which we postulate to disrupt the binding site of a skeletal muscle specific, longrange regulatory element. Here, we overview our current understanding of the molecular mechanisms underlying polar overdominance and provide evidence that this genetic phenomenon is the result of a combination of the cis effect of the callipyge mutation with the trans interaction of reciprocally imprinted gene products.

Authors
Davis, E; Georges, M; Charlier, C
MLA Citation
Davis, E, Georges, M, and Charlier, C. "The callipyge phenomenon: Cis effects, trans effects, and polar overdominance." Annales de Medecine Veterinaire 150.1 (2006): 64-70.
Source
scival
Published In
Annales de medecine veterinaire
Volume
150
Issue
1
Publish Date
2006
Start Page
64
End Page
70

RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus.

The Dlk1-Gtl2 imprinted domain, encompassing the callipyge (CLPG) locus in sheep, has recently been shown to harbor a large number of maternally expressed miRNA genes [1, 2]. Two of these (mir127 and mir136) are processed from a transcript (antiPeg11) that is antisense to Rtl1/Peg11, a paternally expressed intronless gene with homology to the gag and pol polyproteins of Sushi-like retroelements [3]. We herein demonstrate that several additional miRNAs are processed from antiPeg11 and that these regulate Rtl1/Peg11 in trans by guiding RISC-mediated cleavage of its mRNA. This is the first demonstration of miRNA-mediated RNAi involving imprinted genes in mammals.

Authors
Davis, E; Caiment, F; Tordoir, X; Cavaillé, J; Ferguson-Smith, A; Cockett, N; Georges, M; Charlier, C
MLA Citation
Davis, E, Caiment, F, Tordoir, X, Cavaillé, J, Ferguson-Smith, A, Cockett, N, Georges, M, and Charlier, C. "RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus." Curr Biol 15.8 (April 26, 2005): 743-749.
PMID
15854907
Source
pubmed
Published In
Current Biology
Volume
15
Issue
8
Publish Date
2005
Start Page
743
End Page
749
DOI
10.1016/j.cub.2005.02.060

Erratum: RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus (Current Biology (April 26, 2005) (746))

Authors
Davis, E; Caiment, F; Tordoir, X; Cavaillé, J; Ferguson-Smith, A; Cockett, N; Georges, M; Charlier, C
MLA Citation
Davis, E, Caiment, F, Tordoir, X, Cavaillé, J, Ferguson-Smith, A, Cockett, N, Georges, M, and Charlier, C. "Erratum: RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus (Current Biology (April 26, 2005) (746))." Current Biology 15.9 (2005): 884--.
Source
scival
Published In
Current Biology
Volume
15
Issue
9
Publish Date
2005
Start Page
884-
DOI
10.1016/j.cub.2005.04.047

Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype.

The callipyge (CLPG) phenotype is an inherited skeletal muscle hypertrophy described in sheep. It is characterized by an unusual mode of inheritance ("polar overdominance") in which only heterozygous individuals having received the CLPG mutation from their father (+(MAT)/CLPG(PAT)) express the phenotype . +(MAT)/CLPG(PAT) individuals are born normal and develop the muscular hypertrophy at approximately 1 month of age. The CLPG mutation was identified as an A to G transition in a highly conserved dodecamer motif located between the imprinted DLK1 and GTL2 genes . This motif is thought to be part of a long-range control element (LRCE) because the CLPG mutation was shown, in postnatal skeletal muscle, to enhance the transcript levels of the DLK1, PEG11, GTL2, and MEG8 genes in cis without altering their imprinting status . As a result, the +(MAT)/CLPG(PAT) individuals have a unique expression profile thought to underlie the callipyge phenotype: an overexpression of the paternally expressed protein encoding DLK1 (Figure 1A) and PEG11 transcripts in the absence of an overexpression of the maternally expressed noncoding GTL2 and MEG8 transcripts . However, the way in which this distinct expression profile causes the callipyge muscular hypertrophy has remained unclear. Herein, we demonstrate that the callipyge phenotype is perfectly correlated with ectopic expression of DLK1 protein in hypertrophied muscle of +(MAT)/CLPG(PAT) sheep. We demonstrate the causality of this association by inducing a generalized muscular hypertrophy in transgenic mice that express DLK1 in skeletal muscle. The absence of DLK1 protein in skeletal muscle of CLPG/CLPG animals, despite the presence of DLK1 mRNA, supports a trans inhibition mediated by noncoding RNAs expressed from the maternal allele.

Authors
Davis, E; Jensen, CH; Schroder, HD; Farnir, F; Shay-Hadfield, T; Kliem, A; Cockett, N; Georges, M; Charlier, C
MLA Citation
Davis, E, Jensen, CH, Schroder, HD, Farnir, F, Shay-Hadfield, T, Kliem, A, Cockett, N, Georges, M, and Charlier, C. "Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype." Curr Biol 14.20 (October 26, 2004): 1858-1862.
PMID
15498495
Source
pubmed
Published In
Current Biology
Volume
14
Issue
20
Publish Date
2004
Start Page
1858
End Page
1862
DOI
10.1016/j.cub.2004.09.079

Toward molecular understanding of polar overdominance at the ovine callipyge locus.

Authors
Georges, M; Charlier, C; Smit, M; Davis, E; Shay, T; Tordoir, X; Takeda, H; Caiment, F; Cockett, N
MLA Citation
Georges, M, Charlier, C, Smit, M, Davis, E, Shay, T, Tordoir, X, Takeda, H, Caiment, F, and Cockett, N. "Toward molecular understanding of polar overdominance at the ovine callipyge locus." Cold Spring Harb Symp Quant Biol 69 (2004): 477-483. (Review)
PMID
16117683
Source
pubmed
Published In
Cold Spring Harbor Laboratory: Symposia on Quantitative Biology
Volume
69
Publish Date
2004
Start Page
477
End Page
483
DOI
10.1101/sqb.2004.69.477
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Research Areas:

  • Abnormalities, Multiple
  • Adolescent
  • Alleles
  • Animals
  • Animals, Genetically Modified
  • Antigens, Neoplasm
  • Axoneme
  • Bardet-Biedl Syndrome
  • Base Sequence
  • Body Patterning
  • Bone and Bones
  • Brain
  • Caenorhabditis elegans
  • Cardiomyopathies
  • Cell Line
  • Cell Polarity
  • Cells, Cultured
  • Cerebellar Ataxia
  • Cerebellar Diseases
  • Cerebellum
  • Chaperonins
  • Child
  • Chromatography, High Pressure Liquid
  • Cilia
  • Ciliary Motility Disorders
  • Cohort Studies
  • Conserved Sequence
  • Craniosynostoses
  • Cytoskeletal Proteins
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • DNA, Intergenic
  • Diagnosis
  • Disease
  • Disease Models, Animal
  • Early Diagnosis
  • Embryo, Mammalian
  • Embryo, Nonmammalian
  • Encephalocele
  • Epistasis, Genetic
  • Eukaryota
  • Evolution, Molecular
  • Eye Abnormalities
  • Family Health
  • Fibroblasts
  • Gastrulation
  • Gene Deletion
  • Gene Duplication
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression Regulation, Developmental
  • Gene Frequency
  • Gene Knockdown Techniques
  • Genes, Dominant
  • Genes, Helminth
  • Genes, Recessive
  • Genes, X-Linked
  • Genetic Association Studies
  • Genetic Diseases, Inborn
  • Genetic Heterogeneity
  • Genetic Load
  • Genetic Loci
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genetic Therapy
  • Genetic Variation
  • Genetic Vectors
  • Genetics, Medical
  • Genome, Human
  • Genotype
  • Green Fluorescent Proteins
  • HEK293 Cells
  • Hand Deformities, Congenital
  • Heart Defects, Congenital
  • Hedgehog Proteins
  • Hirschsprung Disease
  • Homozygote
  • Human genetics
  • Humans
  • Immediate-Early Proteins
  • Immunohistochemistry
  • Infant
  • Inheritance Patterns
  • Intracellular Signaling Peptides and Proteins
  • Jaw Abnormalities
  • Kartagener Syndrome
  • Kidney
  • Kidney Diseases, Cystic
  • Leukoencephalopathies
  • Mice
  • Microinjections
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Models, Animal
  • Molecular Sequence Data
  • Molecular genetics
  • Morphogenesis
  • Multiprotein Complexes
  • Muscle, Skeletal
  • Muscular Diseases
  • Mutation
  • Mutation, Missense
  • Myocardium
  • Neurons, Afferent
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides, Antisense
  • Otx Transcription Factors
  • Pedigree
  • Penetrance
  • Phenotype
  • Photoreceptor Cells
  • Polymorphism, Single Nucleotide
  • Proteins
  • Proteome
  • Proteomics
  • RNA
  • Respiratory System
  • Retina
  • Retinal Degeneration
  • Retinitis Pigmentosa
  • Ribosomal Proteins
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Situs Inversus
  • Syndrome
  • Systems Biology
  • Transcription Factors
  • Transcription, Genetic
  • Vertebrates
  • Wnt Proteins
  • Zebrafish