The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome.

Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.

High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations.

Joubert syndrome (JS) is an autosomal recessive disorder that is described in patients with cerebellar ataxia, mental retardation, hypotonia, and neonatal respiratory dysregulation. Kidney involvement (nephronophthisis or cystic renal dysplasia) is associated with JS in one fourth of known cases. Mutations in three genes--AHI1, NPHP1, and NPHP6--have been identified in patients with JS. However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood. In an attempt to identify such genetic determinants, a cohort of 28 families with nephronophthisis and at least one JS-related neurologic symptom were screened for mutations in AHI1, NPHP1, and NPHP6 genes. NPHP1 and NPHP6 homozygous or compound heterozygous mutations were found in 13 (46%) and six (21%) unrelated patients, respectively. Two of the 13 patients with NPHP1 mutations carried either a heterozygous truncating mutation in NPHP6 or a heterozygous missense mutation in AHI1. Furthermore, five patients with NPHP1 mutations carried the AHI1 variant R830W, which was predicted to be "possibly damaging" and was found with significantly higher frequency than in healthy control subjects and in patients with NPHP1 mutations without neurologic symptoms (five of 26 versus four of 276 and three of 152 alleles; P < 0.001 and P < 0.002, respectively). In contrast to the variable neurologic and milder retinal phenotype of patients with NPHP1 mutations, patients with NPHP6 mutations presented with a more severe neurologic and retinal phenotype. In conclusion, NPHP1 and NPHP6 are major genes of nephronophthisis associated with JS. Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations.