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

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Authors

CHAKI Moumita AIRIK Rannar GHOSH Amiya K. GILES Rachel H. CHEN Rui SLAATS Gisela G. WANG Hui HURD Toby W. ZHOU Weibin CLUCKEY Andrew GEE Heon-Yung RAMASWAMI Gokul HONG Chen-Jei HAMILTON, Bruce A. ČERVENKA Igor GANJI Sri Ranjani BRYJA Vítězslav ARTS Heleen H. VAN REEUWIJK Jeroen OUD Machteld M. LETTEBOER Stef J.F. ROEPMAN Ronald HUSSON Hervé IBRAGHIMOV-BESKROVNAYA Oxana YSUNAGA Takayuky WALZ Gerd ELEY Lorraine SCHERMER Bernhard SYAER John A. LIEBAU Max C. BENZING Thomas LE CORRE Stephanie DRUMMOND Iain JANSSEN Sabine ALLEN Susan J. NATARAJAN Sivakumar O TOOLE John F. ATTANASIO Massimo SAUNIER Sophie ANTIGNAC Corinne KOENEKOOP Robert K. REN Huanan LOPEZ Irma NAYIR Ahmet STOETZEL Corinne DOLLFUS Helene MASSOUDI Rustin GLEESON Joseph G. ANDREOLI Sharon P. DOHERTY Dan G. LINDSTRAD Anna GOLZIO Christelle KATSANIS Nicholas PAPE Lars ABBOUD Emad B. AL-RAJHI Ali A. LEWIS Richard A. OMRAN Heymut LEE Eva WANG Shaohui SEKIGUCHI JoAnn M. SAUNDERS Rudel JOHNSON Colin A. GARNER Elizabeth VANSELOW Katja ANDERSEN Jens S. SHLOMAI Joseph NURNBERG Gudrun NURNBERG Peter LEVY Shawn SMOGORZEWSKA Agata OTTO Edgar A. HILDEBRANDT Friedhelm

Year of publication 2012
Type Article in Periodical
Magazine / Source Cell
MU Faculty or unit

Faculty of Science

Citation
Doi http://dx.doi.org/10.1016/j.cell.2012.06.028
Field Physiology
Keywords NPHP; CEP 164; ZNF423; renal ciliopathies
Description 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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