Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
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SourceNature Genetics, 39, 7, (2007), pp. 882-8
Article / Letter to editor
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SubjectDCN 1: Perception and Action; DCN 2: Functional Neurogenomics; IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 5: Health aging / healthy living; IGMD 9: Renal disorder; NCMLS 5: Membrane transport and intracellular motility; NCMLS 6: Genetics and epigenetic pathways of disease; UMCN 3.3: Neurosensory disorders; UMCN 5.1: Genetic defects of metabolism
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). 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.
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