title: Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
authors.forename: Jan
authors.initials: J
authors.lastname: Hellemans
authors.forename: Ralf
authors.initials: R
authors.lastname: Sudbrak
authors.forename: Shuling
authors.initials: S
authors.lastname: Fan
authors.forename: Ulla
authors.initials: U
authors.lastname: Muerb
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Juliana
authors.initials: J
authors.lastname: Helou
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: Boris
authors.initials: B
authors.lastname: Utsch
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
authors.forename: Concepcion
authors.initials: C
authors.lastname: Lillo
authors.forename: David
authors.initials: D
authors.lastname: Jimeno
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: Sven
authors.initials: S
authors.lastname: Klages
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Tsuda
authors.forename: Isao
authors.initials: I
authors.lastname: Kawakami
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Anita
authors.initials: A
authors.lastname: Imm
authors.forename: Melissa
authors.initials: M
authors.lastname: Tippens
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Raymond
authors.forename: Jo
authors.initials: J
authors.lastname: Hill
authors.forename: Phil
authors.initials: P
authors.lastname: Beales
authors.forename: Shirley
authors.initials: S
authors.lastname: He
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Margolis
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000595:Amino Acid Sequence; D015152:Blotting, Northern; D002147:Calmodulin / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D020798:Two-Hybrid System Techniques
chemical_list: D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D005136:Eye Proteins; C498171:IQCB1 protein, human; C099929:RPGR protein, human