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

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. Joubert syndrome is an autosomal recessive multisystem disease characterized by cerebellar ataxia, developmental delay, hypotonia, irregular breathing pattern, eye movement abnormalities 1 and cerebellar vermis hypoplasia and dysplasia with accompanying brainstem defects. When visualized on axial images using magnetic resonance imaging (MRI), the brainstem defects give rise to the 'molar tooth sign' (MTS) 2. A related disorder, CORS, is defined by the features of Joubert syndrome with the addition of one or more of the following: renal involvement (nephronophthisis or cystic renal dysplasia), retinal dystrophy, coloboma, polydactyly or liver fibrosis. Nephronophthisis (NPHP), the most common genetic cause of chronic renal failure in children, is characterized by interstitial fibrosis and medullary cyst formation. Disease-causing mutations have been identified in six genes (NPHP1-NPHP6) whose protein products are known to localize to primary cilia 3-5. Joubert syndrome is a genetically heterogeneous condition with recessive mutations in two known genes: AHI1 (ref. 6) and NPHP6 (also known as CEP290) 4,5. In addition, a homozygous NPHP1 deletion shown to be the most common cause of juvenile NPHP has been identified in a subset of individuals with NPHP and Joubert syndrome 7-9 who present with a milder form of the neurological symptoms 10. Two more loci, JBTS1 (CORS1; ref. 11) and JBTS2 (CORS2; ref. 12), have been mapped to chromosomes 9q34.3 and 11p12-11q13.3, respectively.