6533b7dafe1ef96bd126e3d0

RESEARCH PRODUCT

Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.

Uwe WolfrumDan DohertyStef J.f. LetteboerFederico M. FarinIan A. GlassTheo A. PetersKrysta VoesenekMelissa A. ParisiSylvia E. C. Van BeersumRonald RoepmanFrans P.m. CremersTina MärkerHan G. BrunnerNicholas T. GordenHamit ÖZyürekNine V A M KnoersHester Y. KroesHeleen H. ArtsAileen Kartono

subject

AdultMaleHealth aging / healthy living [IGMD 5]Eye DiseasesGenetics and epigenetic pathways of disease [NCMLS 6]TMEM67Molecular Sequence DataMembrane transport and intracellular motility [NCMLS 5]Biologymedicine.disease_causeJoubert syndromeCell LineGenomic disorders and inherited multi-system disorders [IGMD 3]NephronophthisisCerebellar DiseasesGeneticsmedicinePerception and Action [DCN 1]Basal bodyAnimalsHumansNeurosensory disorders [UMCN 3.3]CiliaAdaptor Proteins Signal TransducingRenal disorder [IGMD 9]GeneticsMutationCiliumCiliary transition zoneProteinsSyndromemedicine.diseasePedigreeRatsCytoskeletal ProteinsGenetic defects of metabolism [UMCN 5.1]RPGRIP1LFemaleKidney DiseasesFunctional Neurogenomics [DCN 2]Ciliary Motility Disorders

description

Peters, T.A./0000-0001-8443-5500; van Beersum, Sylvia E.C./0000-0002-4552-2908; Cremers, Frans/0000-0002-4954-5592; Roepman, Ronald/0000-0002-5178-8163 WOS: 000247619800019 PubMed: 17558407 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- Loken syndrome ( SLSN) or Joubert syndrome ( JBTS)(1-6). 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(7,8). 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. NCRR NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [K12-RR023265]; NICHD NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [P30 HD02274, K24-HD46712]; NIEHS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [P30ES07033]; NINDS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [K23-NS45832]

yearjournalcountryeditionlanguage
2007-01-01
10.1038/ng2069https://hdl.handle.net/2066/53630