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

• Published in: Nature genetics Vol. 39; no. 7; pp. 875 - 881
• Main Authors: Delous, Marion, Baala, Lekbir, Salomon, Rémi, Laclef, Christine, Vierkotten, Jeanette, Tory, Kàlmàn, Golzio, Christelle, Lacoste, Tiphanie, Besse, Laurianne, Ozilou, Catherine, Moutkine, Imane, Hellman, Nathan E, Anselme, Isabelle, Silbermann, Flora, Vesque, Christine, Gerhardt, Christoph, Rattenberry, Eleanor, Wolf, Matthias T F, Gubler, Marie Claire, Martinovic, Jéléna, Encha-Razavi, Féréchté, Boddaert, Nathalie, Gonzales, Marie, Macher, Marie Alice, Nivet, Hubert, Champion, Gérard, Berthélémé, Jean Pierre, Niaudet, Patrick, McDonald, Fiona, Hildebrandt, Friedhelm, Johnson, Colin A, Vekemans, Michel, Antignac, Corinne, Rüther, Ulrich, Schneider-Maunoury, Sylvie, Attié-Bitach, Tania, Saunier, Sophie
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2007; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cerebellar Diseases - genetics; Child; Ciliary Motility Disorders - genetics; Complex syndromes; Complications and side effects; Developmental disabilities; Diagnosis; Disease Models, Animal; Encephalocele - genetics; Eye Diseases - genetics; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Function; Gene mutations; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Human Genetics; Humans; Identification and classification; Inactivation; Joubert syndrome; Kidney Diseases - genetics; letter; Malformations of the nervous system; Medical genetics; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Mutant Strains; Mutation; Neurology; Physiological aspects; Point Mutation; Proteins; Proteins - genetics; Risk factors; Rodents; Syndrome; France; Nervous system diseases; Urinary system disease; Joubert syndrome; Diseases of the osteoarticular system; Kidney; Syndrome; Cerebral disorder; Genetic disease; Urinary system; Gene; Malformation; Central nervous system disease; Digestive diseases; Meckel syndrome
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng2039

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.