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


Journal Article

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.

Full Text

Cited Authors

  • 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, C-J; Hamilton, BA; Cervenka, I; Ganji, RS; Bryja, V; Arts, HH; van Reeuwijk, J; Oud, MM; Letteboer, SJF; Roepman, R; Husson, H; Ibraghimov-Beskrovnaya, O; Yasunaga, T; Walz, G; Eley, L; Sayer, JA; Schermer, B; Liebau, MC; Benzing, T; Le Corre, S; Drummond, I; 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, EY-HP; 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

Published Date

  • August 3, 2012

Published In

Volume / Issue

  • 150 / 3

Start / End Page

  • 533 - 548

PubMed ID

  • 22863007

Pubmed Central ID

  • 22863007

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2012.06.028


  • eng

Conference Location

  • United States