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Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling |
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| Authors: | 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 Cervenka 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 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 |
| Institution: | 1 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA 2 Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA 3 Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands 4 HGSC Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 5 Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA 6 Department of Medicine, Division of Medical Genetics, Department of Cellular and Molecular Medicine, and Institute for Genomic Medicine, George Palade Laboratories, Room 256, UCSD School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA 7 Institute of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic 8 Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic 61265 Brno, Czech Republic 9 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6525 GA, Nijmegen, The Netherlands 10 Genzyme Corporation, Cell Biology, Framingham, MA 01701, USA 11 Renal Division, University Freiburg Medical Center, 7900 Freiburg, Germany 12 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK 13 Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, 50937 Cologne, Germany 14 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50937 Cologne, Germany 15 Department of Pediatrics and Adolescent Medicine, University of Cologne, 50937 Cologne, Germany 16 Systems Biology of Aging, University of Cologne, 50937 Cologne, Germany 17 Cologne Center for Genomics and for Molecular Medicine, University of Cologne, 50937 Cologne, Germany 18 Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel 19 Nephrology Division, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Charlestown, MA 02129, USA 20 Division of Nephrology, Department of Internal Medicine, MetroHealth Medical Center, and Case Western Reserve University School of Medicine, Cleveland, OH 44109-1998, USA 21 Department of Internal Medicine and Eugene McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas TX 75390, USA 22 Inserm U983, Paris Descartes University, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France 23 McGill Ocular Genetics Laboratory, Montreal Children’s Hospital, McGill University Health Centre, Montreal, H3H 1P3, Canada 24 Department of Pediatric Nephrology, Faculty of Medicine, University of Istanbul, Istanbul, Turkey 25 Laboratoire de Génétique Médicale EA3949, Equipe AVENIR-Inserm, Faculté de Médecine, Université de Strasbourg, 11 rue Humann, 67000 Strasbourg, France 26 Howard Hughes Medical Institute, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA 27 Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University Medical Center, Indianapolis, IN 46202, USA 28 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Center for Integrative Brain Research, Seattle Children’s Hospital, Seattle, WA, 98101 USA 29 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA 30 Department of Pediatric Nephrology, Hannover Medical School, Hannover 30625, Germany 31 King Khaled Eye Specialist Hospital, Riyadh 11462, Kingdom of Saudi Arabia 32 Klinik und Poliklinik für Kinder- und Jugendmedizin, Allgemeine Pädiatrie, Universitätsklinikum Münster, Münster 48149, Germany 33 University of California Irvine, Department of Biological Chemistry, Irvine, CA 92697, USA 34 Leeds Institute of Molecular Medicine, St James’s University Hospital, Leeds, LS9 7TF, UK 35 Laboratory of Genome Maintenance, The Rockefeller University, New York, NY 10065, USA 36 Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230, Odense, Denmark 37 HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA 38 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA |
| 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. PAPERFLICK: |
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