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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We thank families and study subjects for their contributions and E. Nigg for the OFD1 antibody. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to H.K. (EY007961), to D.S.W. (EY13408), to N.K. (HD042601, DK075972, DK072301) and to E.A.P. (EY12910); by grants from the Netherlands Organization for Scientific Research to K.L.M.C. (NWO Toptalent-021.001.014), to R.R. (NWO Vidi-91786396) and to R.H.G. (NWO Vidi-917.66.354); by the WellChild and Wellcome Trust to E.R.M.; by the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et Déficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007 and the Association Bardet-Biedl, France to H.D., C.S. and E.A.P. by the Foundation Fighting Blindness, the Research to Prevent Blindness, the F.M. Kirby Foundation and the Rosanne Silbermann Foundation to E.A.P.; by the Midwest Eye Banks and Transplantation Center and Rare Disease Initiative, University of Michigan to H.K.; by Instituto Gulbenkian de Ciência and EMBO to M.B.D.; by the Deutsche Nierenstiftung, PKD Foundation and DFG (BE 3910/5-1 and SFB/TRR57) to C.B.; by CIHR, FFB-Canada, FRSQ and Reseau Vision to R.K.K.; by the “Else Kröner-Fresenius-Stiftung” (P66/09//A75/09) to H.P.H.N.; and by EU FP7 Consortium “SYSCILIA” to R.H.G., R.R. and N.K. F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick G. L. Huetwell Professor. D.S.W. is a Jules and Doris Stein RPB professor. N.K. is a George R. Brumley Professor. S.S. is a laureate of the Equipe FRM (Dequation (20071210558)) and the Agence National de la Recherche (R07089KS). We thank the physicians who contributed to this study; A. Toutain, M.-C. Gubler, R. Salomon, M.-A. Macher and M. Fischbach for clinical data; S.J. Allen, A. Saveliev and Y. Liu for technical assistance; K. Tory and C. Becker for linkage analysis and exon sequencing; S. Shi and R. Insolera for shRNA clones; C. Janke for the GT335 antibody; J. Salisbury for the centrin-2 antibody; E. Nigg for the CEP164 antibody; and B. Chang for the CEP290 antibody.
Supplementary Figures 1–10 and Supplementary Tables 1–3.