Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR. PaperFlick:
Bibliographical noteFunding Information:
We are grateful to the study individuals for their contributions. This research was supported by grants from the NIH to F.H. (DK068306, DK090917), B.A.H (NS054871, NS060109), N.K. (HD042601, DK075972, DK072301), and W.Z. (DK091405); the March of Dimes Foundation and the Center for Organogenesis of the University of Michigan to F.H.; the Netherlands Organization for Scientific Research to R.R. (NWO Vidi-91786396) and R.H.G. (NWO Vidi-917.66.354), 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. and C.S.; the European Community's Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA (to R.H.G., G.G.S., N.K., R.R., H.O., C.A.J. and G.W.); the Dutch Kidney Foundation (KJPB09.009 and IP11.58 to H.H.A); the Retina Research Foundation and the National Eye Institute (R01EY018571) to R.C.; the NIH to H.W. (F32EY19430); and the DFG (SCHE1562 and SFB832 to B.S.; SFB829 to T.B.; SFB592 to H.O.). R.K.K. is supported by FFB-Canada, CIHR, FRSQ, and Reseau Vision. J.S.A. is supported by the Lundbeck Foundation. V.B. is supported by MSM0021622430 (Ministry of Education, Youth and Sports of the Czech Republic), 204/09/H058, and 204/09/0498 (Czech Science Foundation) and EMBO Installation Grant; I.C. is supported by the programme, Brno PhD Talent of South Moravian Center for International Mobility. S.S. is a laureate of the “Equipe FRM” (DEQ20071210558) and the Agence National de la Recherche (R09087KS, R11012KK). W.Z. is a Carl. W. Gottschalk research scholar of the American Society of Nephrology. J.A.S. is a GlaxoSmithKline clinician scientist. A.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the Doris Duke Charitable Foundation Clinical Scientist Development Awards and is a Rita Allen Foundation and an Irma T. Hirschl scholar. F.H. is an Investigator of the Howard Hughes Medical Institute, a Frederick G. L. Huetwell Professor, and a Doris Duke Distinguished Clinical Scientist.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)