Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Edgar A. Otto, Bart Loeys, Hemant Khanna, Jan Hellemans, Ralf Sudbrak, Shuling Fan, Ulla Muerb, John F. O'Toole, Juliana Helou, Massimo Attanasio, Boris Utsch, John A. Sayer, Concepcion Lillo, David Jimeno, Paul Coucke, Anne De Paepe, Richard Reinhardt, Sven Klages, Motoyuki Tsuda, Isao KawakamiTakehiro Kusakabe, Heymut Omran, Anita Imm, Melissa Tippens, Pamela A. Raymond, Jo Hill, Phil Beales, Shirley He, Andreas Kispert, Benjamin Margolis, David S. Williams, Anand Swaroop, Friedhelm Hildebrandt

Research output: Contribution to journalArticlepeer-review

306 Scopus citations


Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children1-3. 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. IQCBI 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.

Original languageEnglish (US)
Pages (from-to)282-288
Number of pages7
JournalNature genetics
Issue number3
StatePublished - 2005

ASJC Scopus subject areas

  • Genetics


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