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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 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.

Pubmed ID: 15723066


  • Otto EA
  • Loeys B
  • Khanna H
  • Hellemans J
  • Sudbrak R
  • Fan S
  • Muerb U
  • O'Toole JF
  • Helou J
  • Attanasio M
  • Utsch B
  • Sayer JA
  • Lillo C
  • Jimeno D
  • Coucke P
  • De Paepe A
  • Reinhardt R
  • Klages S
  • Tsuda M
  • Kawakami I
  • Kusakabe T
  • Omran H
  • Imm A
  • Tippens M
  • Raymond PA
  • Hill J
  • Beales P
  • He S
  • Kispert A
  • Margolis B
  • Williams DS
  • Swaroop A
  • Hildebrandt F


Nature genetics

Publication Data

March 25, 2005

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK084725
  • Agency: NEI NIH HHS, Id: R01 EY007042

Mesh Terms

  • Amino Acid Sequence
  • Blotting, Northern
  • Calmodulin
  • Calmodulin-Binding Proteins
  • Eye Proteins
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Syndrome
  • Two-Hybrid System Techniques