Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children(1-3). Identification of four genes mutated in NPHP subtypes 1- 4 (refs. 4- 9) has linked the pathogenesis of NPHP to ciliary functions(9). 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.
Hildebrandt, F. Nephronophthisis—medullary cystic kidney disease. in Pediatric Nephrology (eds. Avner, E.D. & Niaudet, P.) 665–673 (Lippincott, Williams & Wilkins, Philadelphia, 2004).
Hildebrandt Friedhelm, Otto Edgar, Rensing Cornelia, Nothwang Hans Gerd, Vollmer Martin, Adolphs Jörn, Hanusch Helge, Brandis Matthias, A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1, 10.1038/ng1097-149
Saunier S, A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis, 10.1093/hmg/6.13.2317
Otto Edgar, Hoefele Julia, Ruf Rainer, Mueller Adelheid M., Hiller Karl S., Wolf Matthias T.F., Schuermann Maria J., Becker Achim, Birkenhäger Ralf, Sudbrak Ralf, Hennies Hans C., Nürnberg Peter, Hildebrandt Friedhelm, A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution, 10.1086/344395
Mollet Géraldine, Salomon Rémi, Gribouval Olivier, Silbermann Flora, Bacq Delphine, Landthaler Gilbert, Milford David, Nayir Ahmet, Rizzoni Gianfranco, Antignac Corinne, Saunier Sophie, The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin, 10.1038/ng996
Olbrich Heike, Fliegauf Manfred, Hoefele Julia, Kispert Andreas, Otto Edgar, Volz Andreas, Wolf Matthias T, Sasmaz Gürsel, Trauer Ute, Reinhardt Richard, Sudbrak Ralf, Antignac Corinne, Gretz Norbert, Walz Gerd, Schermer Bernhard, Benzing Thomas, Hildebrandt Friedhelm, Omran Heymut, Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis, 10.1038/ng1216
Otto Edgar A, Schermer Bernhard, Obara Tomoko, O'Toole John F, Hiller Karl S, Mueller Adelheid M, Ruf Rainer G, Hoefele Julia, Beekmann Frank, Landau Daniel, Foreman John W, Goodship Judith A, Strachan Tom, Kispert Andreas, Wolf Matthias T, Gagnadoux Marie F, Nivet Hubert, Antignac Corinne, Walz Gerd, Drummond Iain A, Benzing Thomas, Hildebrandt Friedhelm, Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination, 10.1038/ng1217
Dehal P., The Draft Genome of Ciona intestinalis: Insights into Chordate and Vertebrate Origins, 10.1126/science.1080049
Otto E., J. Am. Soc. Nephrol., 11, 270 (2000)
Morgan David, Goodship Judith, Essner Jeffrey J., Vogan Kyle J., Turnpenny Lee, Yost Joseph H., Tabin Clifford J., Strachan Tom, The left-right determinant inversin has highly conserved ankyrin repeat and IQ domains and interacts with calmodulin, 10.1007/s00439-002-0696-4
Hong Dong-Hyun, Pawlyk Basil, Sokolov Maxim, Strissel Katherine J., Yang Jun, Tulloch Brian, Wright Alan F., Arshavsky Vadim Y., Li Tiansen, RPGR Isoforms in Photoreceptor Connecting Cilia and the Transitional Zone of Motile Cilia, 10.1167/iovs.02-1206
Wright Alan F., Vervoort Raf, Lennon Alan, Bird Alan C., Tulloch Brian, Axton Richard, Miano Maria G., Meindl Alfons, Meitinger Thomas, Ciccodicola Alfredo, 10.1038/78182
Breuer Debra K., Yashar Beverly M., Filippova Elena, Hiriyanna Suja, Lyons Robert H., Mears Alan J., Asaye Bersabell, Acar Ceren, Vervoort Raf, Wright Alan F., Musarella Maria A., Wheeler Patricia, MacDonald Ian, Iannaccone Alessandro, Birch David, Hoffman Dennis R., Fishman Gerald A., Heckenlively John R., Jacobson Samuel G., Sieving Paul A., Swaroop Anand, A Comprehensive Mutation Analysis of RP2 and RPGR in a North American Cohort of Families with X-Linked Retinitis Pigmentosa, 10.1086/340848
Roepman R., The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors, 10.1093/hmg/9.14.2095
Cuenca Nicolas, Deng Ping, Linberg Ken A., Lewis Geoffrey P., Fisher Steven K., Kolb Helga, 10.1023/a:1025791512555
Chen T.Y., Proc. Natl Acad. Sci. USA, 91, 11757 (1994)
Besharse, J.C. et al. The photoreceptor connecting cilium: a model for the transition zone. in The Photoreceptor Connecting Cilium: A Model for the Transitions Zone (ed. Ra, B.) 409–431 (Plenum, New York, 1990).
Gattone Vincent H, Wang Xiaofang, Harris Peter C, Torres Vicente E, Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist, 10.1038/nm935
Wilkinson, D.G. Whole mount in situ hybridization of vertebrate embryos. in In Situ Hybridization: A Practical Approach (ed. Wilkinson, D.G.) 75–84 (Oxford University Press, Oxford, 1992).
Hong D.H., Invest. Ophthalmol. Vis. Sci., 43, 3373 (2002)
Cheng H., Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors, 10.1093/hmg/ddh173
Gibbs D., Role of myosin VIIa and Rab27a in the motility and localization of RPE melanosomes, 10.1242/jcs.01580
Bibliographic reference
Otto, EA ; et. al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. In: Nature Genetics, Vol. 37, no. 3, p. 282-288 (2005)