Nature Genetics 38, 674 - 681 (2006)
Published online: 7 May 2006; | doi:10.1038/ng1786
The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4John A Sayer1, 2, 22, Edgar A Otto1, 22, John F O'Toole1, Gudrun Nurnberg3, 4, Michael A Kennedy5, Christian Becker3, 4, Hans Christian Hennies3, 20, Juliana Helou1, Massimo Attanasio1, Blake V Fausett6, Boris Utsch1, Hemant Khanna7, Yan Liu8, Iain Drummond8, Isao Kawakami9, Takehiro Kusakabe9, Motoyuki Tsuda9, Li Ma10, Hwankyu Lee11, Ronald G Larson11, Susan J Allen1, Christopher J Wilkinson12, Erich A Nigg12, Chengchao Shou13, Concepcion Lillo14, David S Williams14, Bernd Hoppe15, Markus J Kemper16, Thomas Neuhaus16, Melissa A Parisi17, Ian A Glass17, Marianne Petry18, Andreas Kispert18, Joachim Gloy19, Athina Ganner19, Gerd Walz19, Xueliang Zhu10, Daniel Goldman6, Peter Nurnberg3, 20, Anand Swaroop7, 21, Michel R Leroux5
& Friedhelm Hildebrandt1, 211
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA. 2
Institute of Human Genetics, School of Clinical Medical Sciences, University of Newcastle upon Tyne, NE1 3BZ, UK. 3
Cologne Center for Genomics, University of Cologne, Cologne, Germany. 4
RZPD Deutsches Ressourcenzentrum fuer Genomforschung GmbH, Berlin, Germany. 5
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. 6
Molecular and Behavioral Neuroscience, Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA. 7
Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan 48109, USA. 8
Harvard Medical School and Renal Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. 9
Department of Life Science, Graduate School of Life Science, University of Hyogo, Hyogo 678-1297, Japan. 10
Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Shanghai 200031, China. 11
Departments of Biomedical Engineering and Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA. 12
Max-Planck Institute for Biochemistry, Department of Cell Biology, D-82152 Martinsried, Germany. 13
Department of Biochemistry and Molecular Biology, Peking University School of Oncology, Beijing Institute for Cancer Research, Beijing 100036 PRC, China. 14
Departments of Pharmacology and Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California 92093-9012, USA. 15
Department of Pediatrics, University of Cologne, Cologne, Germany. 16
Department of Pediatrics, University of Zurich, Zurich, Switzerland. 17
Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA. 18
Institute for Molecular Biology, Medizinische Hochschule Hannover, D-30625 Hannover, Germany. 19
University of Freiburg, Freiburg, Germany. 20
Institute for Genetics, University of Cologne, Cologne, Germany. 21
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. 22
These authors contributed equally to this work.
Correspondence should be addressed to Friedhelm Hildebrandt fhilde@umich.edu CEP290The molecular basis of nephronophthisis1, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome2 are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle–dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
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