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

Moumita Chaki, Rannar Airik, Amiya K. Ghosh, Rachel H. Giles, Rui Chen, Gisela G. Slaats, Hui Wang, Toby W. Hurd, Weibin Zhou, Andrew Cluckey, Heon Yung Gee, Gokul Ramaswami, Chen Jei Hong, Bruce A. Hamilton, Igor Červenka, Ranjani Sri Ganji, Vitezslav Bryja, Heleen H. Arts, Jeroen Van Reeuwijk, MacHteld M. OudStef J.F. Letteboer, Ronald Roepman, Hervé Husson, Oxana Ibraghimov-Beskrovnaya, Takayuki Yasunaga, Gerd Walz, Lorraine Eley, John A. Sayer, Bernhard Schermer, Max C. Liebau, Thomas Benzing, Stephanie Le Corre, Iain Drummond, Sabine Janssen, Susan J. Allen, Sivakumar Natarajan, John F. O'Toole, Massimo Attanasio, Sophie Saunier, Corinne Antignac, Robert K. Koenekoop, Huanan Ren, Irma Lopez, Ahmet Nayir, Corinne Stoetzel, Helene Dollfus, Rustin Massoudi, Joseph G. Gleeson, Sharon P. Andreoli, Dan G. Doherty, Anna Lindstrad, Christelle Golzio, Elias Nicholas Katsanis, Lars Pape, Emad B. Abboud, Ali A. Al-Rajhi, Richard A. Lewis, Heymut Omran, Eva Y.H.P. Lee, Shaohui Wang, Joann M. Sekiguchi, Rudel Saunders, Colin A. Johnson, Elizabeth Garner, Katja Vanselow, Jens S. Andersen, Joseph Shlomai, Gudrun Nurnberg, Peter Nurnberg, Shawn Levy, Agata Smogorzewska, Edgar A. Otto, Friedhelm Hildebrandt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

288 Scopus citations


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:

Original languageEnglish (US)
Pages (from-to)533-548
Number of pages16
Issue number3
StatePublished - Aug 3 2012

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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