Nature Genetics
37, 282 - 288 (2005)
Published online: 20 February 2005; | doi:10.1038/ng1520
Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulinEdgar A Otto1, Bart Loeys2, Hemant Khanna3, Jan Hellemans4, Ralf Sudbrak5, 6, Shuling Fan7, Ulla Muerb1, John F O'Toole1, Juliana Helou1, Massimo Attanasio1, Boris Utsch1, John A Sayer1, Concepcion Lillo8, David Jimeno8, Paul Coucke4, Anne De Paepe4, Richard Reinhardt5, Sven Klages5, Motoyuki Tsuda9, Isao Kawakami9, Takehiro Kusakabe9, Heymut Omran10, Anita Imm10, Melissa Tippens11, Pamela A Raymond11, Jo Hill12, Phil Beales12, Shirley He3, Andreas Kispert13, Benjamin Margolis7, David S Williams8, Anand Swaroop3, 14
& Friedhelm Hildebrandt1, 141
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA. 2
McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. 3
Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan 48109, USA. 4
Center for Medical Genetics, Ghent University Hospital, Ghent 9000, Belgium. 5
Max Planck Institute for Molecular Genetics, Berlin, Germany. 6
Institute for Clinical Molecular Biology, Christian Albrechts University, 24105 Kiel, Germany. 7
Howard Hughes Medical Institute and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. 8
Departments of Pharmacology and Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California 92093-0912, USA. 9
Department of Life Science, Graduate School of Life Science, University of Hyogo, Hyogo 678-1297, Japan. 10
University Children's Hospital Freiburg, Freiburg, Germany. 11
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. 12
Molecular Medicine Unit, Institute of Child Health, University College London, London, UK. 13
Institute for Molecular Biology, Medizinische Hochschule Hannover, 30625 Hannover, Germany. 14
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Correspondence should be addressed to Friedhelm Hildebrandt fhilde@umich.eduNephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children1,
2,
3. Identification of four genes mutated in NPHP subtypes 1−4 (refs. 4−9) has linked the pathogenesis of NPHP to ciliary functions9. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10−20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.
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