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|
|Date of Publication (YYYY-MM-DD):||2005-02-20|
|Title of Journal:||Nature Genetics|
|Journal Abbrev.:||Nat Gen|
|Issue / Number:||3|
|Review Status:||not specified|
|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 email@example.com|
|External Publication Status:||published|
|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.
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