Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin |
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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 Reinhardt 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 |
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Affiliation: | Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA. |
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Abstract: | Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. 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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