Journal
CELL
Volume 150, Issue 3, Pages 533-548Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.06.028
Keywords
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Categories
Funding
- NIH [DK068306, DK090917, NS054871, NS060109, HD042601, DK075972, DK072301, DK091405, F32EY19430]
- March of Dimes Foundation
- Center for Organogenesis of the University of Michigan
- Netherlands Organization for Scientific Research [NWO Vidi-91786396, NWO Vidi-917.66.354]
- 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
- European Community [241955, SYSCILIA]
- Dutch Kidney Foundation [KJPB09.009, IP11.58]
- Retina Research Foundation
- National Eye Institute [R01EY018571]
- DFG [SCHE1562, SFB832, SFB829, SFB592]
- FFB-Canada
- CIHR
- FRSQ
- Reseau Vision
- Lundbeck Foundation
- Ministry of Education, Youth and Sports of the Czech Republic [MSM0021622430]
- Czech Science Foundation [204/09/H058, 204/09/0498]
- EMBO Installation Grant
- Brno PhD Talent of South Moravian Center for International Mobility
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Doris Duke Charitable Foundation
- MRC [G0700073] Funding Source: UKRI
- Medical Research Council [G0700073] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
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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.
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