Abstract
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.
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Acknowledgements
We thank the patients and their families for participation. We thank N. Spassky, R. Benkirane, G. Guedu, S. Audollent, C. Gazengel, S. Delahaye and C. Esculpavit for technical assistance and the SOFFOET for clinical data and material support. We thank M. Teboul and the staff of the Centre d'Orthogénie at the Broussais hospital in Paris for their contributions. This work was supported by grants from GIS-Maladies Rares (AAE05017KSA), the Association pour l'Utilisation du Rein Artificiel, the Association pour la Recherche sur le Cancer (ARC) (to S.S.M.) and the Deutsche Forschungsgemeinschaft (DFG) through SFB 590 and 612 (to U.R.). M.D. is the recipient of a fellowship from the Ministère de la Recherche, K.T. and N.E.H. were supported from a grant from the Fondation Recherche Médicale, K.T. benefits from an ERA-EDTA fellowship, N.E.H. is the recipient of a Fulbright grant and L.B. is supported by the CANAM. F.H. is a Doris Duke Distinguished Clinical Scientist and supported by US National Institutes of Health grant DK068306. M.T.F.W. was supported by grants from the German Kidney Fund (Deutsche Nierenstiftung) and the German Research Foundation (DFG WO 1229/2-1).
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The senior authors T.A.-B. and S.S. contributed equally to this work. T.A.-B. and S.S. designed this study; M.D. and C.G. performed expression studies in humans; M.D., F.S. and I.M. performed functional analyses (interaction and localization studies); L.B., T.L., K.T. and C.O. contributed to mutation screening; S.S.-M., C.L., L.B., I.A. and C.V. performed mouse phenotype analyses; U.R., J.V. and C.G. generated mice and antibodies against Rpgrip1l; C.A., R.S., M.C.G., F.E.-R., M.V. and N.B. performed phenotype assessment, C.A.J., F.M., E.R., F.H. and M.T.F.W. contributed to the SNP genotyping; C.A., N.E.H, R.S. and S.S.-M. contributed to the writing of this paper and M.G., M.A.M., H.N., G.C., J.P.B. and P.N. assessed patients in the study. R.S. and S.S.-M. initiated the collaboration.
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Supplementary information
Supplementary Fig. 1
RPGRIP1L mutations in individuals with CORS and fetuses with MKS. (PDF 292 kb)
Supplementary Fig. 2
Anatomical and pathological data from individuals with CORS and fetuses with MKS. (PDF 471 kb)
Supplementary Fig. 3
RPGRIP1L localization during cell division. (PDF 413 kb)
Supplementary Fig. 4
Characterization of polyclonal antibody to nephrocystin-6. (PDF 143 kb)
Supplementary Fig. 5
Characterization of polyclonal antibodies to RPGRIP1L. (PDF 178 kb)
Supplementary Table 1
Exon-flanking oligonucleotide PCR primers for the human RPGRIP1L gene. (PDF 12 kb)
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Delous, M., Baala, L., Salomon, R. et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 39, 875–881 (2007). https://doi.org/10.1038/ng2039
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DOI: https://doi.org/10.1038/ng2039
