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          Institute: MPI für molekulare Genetik     Collection: Sequencing Group     Display Documents



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ID: 272850.0, MPI für molekulare Genetik / Sequencing Group
Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin
Authors:Otto, Edgar A; Loeys, Bart; Khanna, Hemant; Hellemans, Jan; Sudbrak, Ralf; Fan, Shuling; Muerb, Ulla; O'Toole, John F; Helou, Juliana; Attanasio, Massimo; Utsch, Boris; Sayer, John A; Lillo, Concepcion; Jimeno, David; Coucke, Paul; De Paepe, Anne; Reinhard, Richard; Klages, Sven; Tsuda, Motoyuki; Kawakami, Isao; Kusakabe, Takehiro; Omran, Heymut; Imm, Anita; Tippens, Melissa; Raymond, Pamela A; Hill, Jo; Beales, Phil; He, Shirley; Kispert, Andreas; Margolis, Benjamin; Williams, David S.; Swaroop, Anand; Hildebrandt, Friedhelm
Language:English
Date of Publication (YYYY-MM-DD):2005-02-20
Title of Journal:Nature Genetics
Journal Abbrev.:Nat Gen
Volume:37
Issue / Number:3
Start Page:282
End Page:288
Review Status:not specified
Audience:Experts Only
Abstract / Description:Nephronophthisis (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.
Comment of the Author/Creator:Correspondence should be addressed to Friedhelm Hildebrandt fhilde@umich.edu
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Richard Reinhardt
Affiliations:MPI für molekulare Genetik
External Affiliations:Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA,
McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA,
Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan 48109, USA,
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,
Departments of Pharmacology and Neurosciences, School of Medicine, University of California at San Diego, La Jolla, California 92093-0912, USA,
Department of Life Science, Graduate School of Life Science, University of Hyogo, Hyogo 678-1297, Japan,
University Children's Hospital Freiburg, Freiburg, Germany,
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA,
Molecular Medicine Unit, Institute of Child Health, University College London, London, UK,
Institute for Molecular Biology, Medizinische Hochschule Hannover, 30625 Hannover, Germany,
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

4 Center for Medical Genetics, Ghent University Hospital, Ghent 9000, Belgium.
Identifiers:DOI:10.1038/ng1520
ISSN:1061-4036
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