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

TitleExome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.
Publication TypeJournal Article
Year of Publication2012
AuthorsChaki, M, Airik, R, Ghosh, AK, Giles, RH, Chen, R, Slaats, GG, Wang, H, Hurd, TW, Zhou, W, Cluckey, A, Gee, HYung, Ramaswami, G, Hong, C-J, Hamilton, BA, Cervenka, I, Ganji, RSri, 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
JournalCell
Volume150
Issue3
Pagination533-48
Date Published2012 Aug 3
ISSN1097-4172
KeywordsAnimals, Cilia, DNA Damage, DNA-Binding Proteins, Exome, Gene Knockdown Techniques, Genes, Recessive, Humans, Kidney Diseases, Cystic, Mice, Microtubule Proteins, Signal Transduction, Zebrafish
Abstract

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.

DOI10.1016/j.cell.2012.06.028
Alternate JournalCell
PubMed ID22863007
PubMed Central IDPMC3433835
Grant ListDK068306 / DK / NIDDK NIH HHS / United States
DK072301 / DK / NIDDK NIH HHS / United States
DK075972 / DK / NIDDK NIH HHS / United States
DK090917 / DK / NIDDK NIH HHS / United States
DK091405 / DK / NIDDK NIH HHS / United States
F32EY19430 / EY / NEI NIH HHS / United States
G0700073 / / Medical Research Council / United Kingdom
HD042601 / HD / NICHD NIH HHS / United States
K99 DK091405 / DK / NIDDK NIH HHS / United States
NS054871 / NS / NINDS NIH HHS / United States
NS060109 / NS / NINDS NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
R01 DK072301 / DK / NIDDK NIH HHS / United States
R01 DK075972 / DK / NIDDK NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
R01 DK088767 / DK / NIDDK NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
R01 HD042601 / HD / NICHD NIH HHS / United States
R01 NS054871 / NS / NINDS NIH HHS / United States
R01 NS060109 / NS / NINDS NIH HHS / United States
R01EY018571 / EY / NEI NIH HHS / United States
S10 RR026550 / RR / NCRR NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States