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Journal Article

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

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Sudbrak,  Ralf
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

Reinhard,  Richard
Max Planck Society;

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Klages,  Sven
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Otto, E. A., Loeys, B., Khanna, H., Hellemans, J., Sudbrak, R., Fan, S., et al. (2005). Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nature Genetics, 37(3), 282-288. doi:10.1038/ng1520.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0010-86CF-F
Abstract
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.