Journal
NATURE GENETICS
Volume 42, Issue 10, Pages 840-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.662
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Funding
- National Institutes of Health [DK1069274, DK1068306, DK064614, EY007961, EY13408, HD042601, DK075972, DK072301, EY12910]
- Netherlands Organization for Scientific Research (NWO) [Toptalent-021.001.014, Vidi-91786396, Vidi-917.66.354]
- WellChild
- Avenir-INSERM program
- Agence Nationale pour la Recherche
- Union Nationale pour les Aveugles et Deficients Visuels, RETINA France
- Programme Hospitalier de Recherche National
- Association Bardet-Biedl, France
- Foundation Fighting Blindness
- Research to Prevent Blindness
- F. M. Kirby Foundation
- Rosanne Silbermann Foundation
- Midwest Eye Banks and Transplantation Center
- Instituto Gulbenkian de Ciencia
- Deutsche Nierenstiftung
- DFG [BE 3910/5-1, SFB/TRR57]
- CIHR
- Else Kroner-Fresenius-Stiftung [P66/09//A75/09]
- EU
- Wellcome Trust
- Rare Disease Initiative, University of Michigan
- EMBO
- PKD Foundation
- FFB-Canada
- FRSQ
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Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.
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