title: Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
abstract: Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-Løken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.forename: Sylvia E C
authors.initials: SE
authors.lastname: van Beersum
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Parisi
authors.forename: Stef J F
authors.initials: SJ
authors.lastname: Letteboer
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Gorden
authors.forename: Theo A
authors.initials: TA
authors.lastname: Peters
authors.forename: Tina
authors.initials: T
authors.lastname: Märker
authors.forename: Krysta
authors.initials: K
authors.lastname: Voesenek
authors.forename: Aileen
authors.initials: A
authors.lastname: Kartono
authors.forename: Hamit
authors.initials: H
authors.lastname: Ozyurek
authors.forename: Federico M
authors.initials: FM
authors.lastname: Farin
authors.forename: Hester Y
authors.initials: HY
authors.lastname: Kroes
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002460:Cell Line; D002526:Cerebellar Diseases / Q000235:genetics*; D002923:Cilia / Q000235:genetics*; D002925:Ciliary Motility Disorders / Q000235:genetics*; D003598:Cytoskeletal Proteins; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D013577:Syndrome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C491578:NPHP4 protein, human; D011506:Proteins; C415903:RPGRIP1 protein, human; C532826:RPGRIP1L protein, human