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.

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

“…The INPP5E phenotypic spectrum appears to largely overlap with that related to AHI1 mutations; 18 conversely, none of the INPP5E-mutated patients presented polydactyly or encephalocele, two features that are often associated with mutations in genes also causative of MKS, such as TMEM216, CEP290, TMEM67 or RPGRIP1L. 5,[19][20][21] In one patient with pure JS (COR28), only a single heterozygous INPP5E mutation could be detected, despite complete sequencing of the coding regions and canonical splice sites, and search for genomic rearrangements. Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene.…”

Cerebellar development and disease

“…These include Ableson-helper integration-1 (AHI1), Nephrocystin-1 (NPHP1), Centrosomal protein-290 (CEP290), Transmembrane protein 67 (TMEM67) and Retinitis pigmentosa GTPase regulator-interacting protein-like (RPGRIP1L). Each of the genes encodes a modular scaffolding protein without clear enzymatic domains, but sharing several protein-interaction domains of unknown function, suggesting that they may be part of a signaling complex [28][29][30][31][32][33][34][35][36] The Joubert syndrome connection with cilia Although the function of JSRD proteins remains largely unknown, recent evidence suggests roles in either mediating the assembly/stability of cilia or mediating cargo transport within cilia. When tested directly, at least three of the encoded proteins, NPHP1, CEP290 and RPGRIP1L have demonstrated localization to the basal body or cilium [32,[35][36][37], further suggesting a role at the cilium or basal body.…”

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…15 In fact, mutations in MKS genes have been reported to cause other ciliopathies, for example, MKS1 and BardetBiedl syndrome, 16 TMEM216 and Joubert syndrome, 17 TMEM67 and Joubert syndrome and nephrophthisis, 18,19 CEP290 in non-syndromic retinal dystrophy, Senior-Loken syndrome, nephronophthisis, Joubert syndrome, and Bardet-Biedl syndrome, 20 RPGRIP1L and Joubert syndrome, 21 and CC2D2A and Joubert syndrome. 22 The factors that determine the ultimate clinical phenotype are not completely understood but there is growing evidence that ciliopathies represent a spectrum of clinical severity that correlates to some extent with the severity of the ciliary defect.…”