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Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling

Lookup NU author(s): Dr Lorraine Eley, Professor John SayerORCiD


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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, hitherto not implicated in ciliopathies. 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 NPHPRC phenotype. We identify TTBK2, CCDC92, NPHP3 and DVL3 as novel CEP164 interaction partners. Our findings link degenerative diseases of kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

Publication metadata

Author(s): Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJF, Roepman R, Husson H, Ibraghimov-Beskrovnaya O, Ysunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, Benzing T, Le Corre S, Drummond I, Joles JA, Janssen S, Allen SJ, Natarajan S, O'Toole JF, Attanasio M, Saunier S, Antignac C, Koenekoop RK, Ren H, Lopez I, Nayir A, Stoetzel C, Dollfus H, Massoudi R, Gleeson JG, Andreoli SP, Doherty DG, Lindstrad A, Golzio C, Katsanis N, Pape L, Abboud EB, Al-Rajhi AA, Lewis RA, Omran H, Lee EYHP, Wang S, Sekiguchi JM, Saunders R, Johnson CA, Garner E, Vanselow K, Andersen JS, Shlomai J, Nurnberg G, Nurnberg P, Levy S, Smogorzewska A, Otto EA, Hildebrandt F

Publication type: Article

Publication status: Published

Journal: Cell

Year: 2012

Volume: 150

Issue: 3

Pages: 533-548

Print publication date: 03/08/2012

ISSN (print): 0092-8674

ISSN (electronic): 1097-4172

Publisher: Cell Press


DOI: 10.1016/j.cell.2012.06.028


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Funder referenceFunder name
Agence Nationale pour la Recherche
Association Bardet-Biedl, France
Burroughs Wellcome Fund Career Award for Medical Scientists
Center for Organogenesis of the University of Michigan
Doris Duke Charitable Foundation
March of Dimes Foundation
Programme Hospitalier de Recherche National
Retina Research Foundation
Avenir-INSERM program
Brno PhD Talent of South Moravian Center for International Mobility
EMBO Installation Grant
Lundbeck Foundation
Reseau Vision
Union Nationale pour les Aveugles et Deficients Visuels
204/09/0498Czech Science Foundation
204/09/H058Czech Science Foundation
241955European Community
KJPB09.009Dutch Kidney Foundation
IP11.58Dutch Kidney Foundation
MSM0021622430Ministry of Education, Youth and Sports of the Czech Republic
NWO Vidi-91786396Netherlands Organization for Scientific Research
R01EY018571National Eye Institute
NWO Vidi-917.66.354Netherlands Organization for Scientific Research
SYSCILIAEuropean Community