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


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. 49) 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.

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Figure 1: Refinement of the IQCB1 gene locus by haplotype analysis in the consanguineous pedigree A132 with SLSN.
Figure 2: Identification of IQCB1 by direct mutational analysis in positional candidates.
Figure 3: Nephrocystin-5 directly interacts with calmodulin and is complexed with RPGR.
Figure 4: Nephrocystin-5 localizes to primary cilia in renal tubular epithelial cells and retinal cells.

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We thank the affected individuals and their families for participation; R.H. Lyons for large-scale sequencing; M. Petry for technical assistance; and G. Feldhoff, T. Bonzel, H.P. Krohn, C.R. Lincke, H. Ruder, M.J. Schuermann, S. Briese, W. Wuyts, A. Raes, Y. Pirson and C. Dahan for contribution of materials and clinical data from affected individuals. This research was supported by grants from US National Institutes of Health to F.H., to A.S. and to D.S.W.; by grants to A.S. from the Foundation Fighting Blindness and Research to Prevent Blindness; and by grants from the German Research Foundation to H.O. F.H. is a Frederick G.L. Huetwell Professor. A.S. is Harold F. Falls Collegiate Professor and recipient of RPB Senior Scientific Investigator Award. B.M. is an investigator of the Howard Hughes Medical Institute. J. Hellemans is funded by the Institute for the Promotion of Innovation by Science and Technology in Flanders. A.K. is supported by grants from the German Research Foundation.

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Correspondence to Friedhelm Hildebrandt.

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Supplementary information

Supplementary Fig. 1

Northern blot analysis of NPHP5. (PDF 298 kb)

Supplementary Fig. 2

Whole-mount in situ hybridization analysis of Nphp5 expression during embryonic development of mouse and C. intestinalis, respectively. (PDF 188 kb)

Supplementary Fig. 3

Amino acid sequence alignment for nephrocystin-5 (NPHP5) orthologs of mouse, rat, human, zebrafish, and C. intestinalis. (PDF 191 kb)

Supplementary Fig. 4

Characterization of anti-NPHP5 antibody by immunoblot analysis. (PDF 178 kb)

Supplementary Fig. 5

Characterization of the anti-ORG15CP antibody. (PDF 228 kb)

Supplementary Table 1

Exon-flanking primers used for PCR in the human NPHP5 gene. (PDF 159 kb)

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Otto, E., Loeys, B., Khanna, H. et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 37, 282–288 (2005).

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