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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. Oud  ;  Stef J.F. Letteboer  ;  Ronald Roepman  ;  Hervé Husson  ;  Oxana Ibraghimov-Beskrovnaya  ;  Takayuki Ysunaga  ;  Gerd Walz  ;  Lorraine Eley  ;  John A. Sayer  ;  Bernhard Schermer  ;  Max C. Liebau  ;  Thomas Benzing  ;  Stephanie Le Corre  ;  Iain Drummond  ;  Jaap A. Joles  ;  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  ;  Nicholas Katsanis  ;  Lars Pape  ;  Emad B. Abboud  ;  Ali A. Al-Rajhi  ;  Richard A. Lewis  ;  James R. Lupski  ;  Heymut Omran 
 CELL, Vol.150(3) : 533-548, 2012 
Journal Title
Issue Date
Animals ; Cilia/metabolism ; DNA Damage* ; DNA-Binding Proteins/metabolism* ; Exome* ; Gene Knockdown Techniques ; Genes, Recessive ; Humans ; Kidney Diseases, Cystic/genetics* ; MRE11 Homologue Protein ; Mice ; Microtubule Proteins/metabolism* ; Signal Transduction ; Zebrafish/embryology ; Zebrafish/metabolism
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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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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