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

Marion Delous; Lekbir Baala; Rémi Salomon; Christine Laclef; Jeanette Vierkotten; Kàlmàn Tory; Christelle Golzio; Tiphanie Lacoste; Laurianne Besse; Catherine Ozilou; Imane Moutkine; Nathan E. Hellman; Isabelle Anselme; Flora Silbermann; Christine Vesque; Christoph Gerhardt; Eleanor Rattenberry; Matthias T F Wolf; Marie Claire Gubler; Jéléna Martinovic; Féréchté Encha-Razavi; Nathalie Boddaert; Marie Gonzales; Marie Alice Macher; Hubert Nivet; Gérard Champion; Jean Pierre Berthélémé; Patrick Niaudet; Fiona McDonald; Friedhelm Hildebrandt; Colin A. Johnson; Michel Vekemans; Corinne Antignac; Ulrich Rüther; Sylvie Schneider-Maunoury; Tania Attié-Bitach; Sophie Saunier

doi:10.1038/ng2039

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

Marion Delous, Lekbir Baala, Rémi Salomon, Christine Laclef, Jeanette Vierkotten, Kàlmàn Tory, Christelle Golzio, Tiphanie Lacoste, Laurianne Besse, Catherine Ozilou, Imane Moutkine, Nathan E. Hellman, Isabelle Anselme, Flora Silbermann, Christine Vesque, Christoph Gerhardt, Eleanor Rattenberry, Matthias T F Wolf, Marie Claire Gubler, Jéléna MartinovicFéréchté Encha-Razavi, Nathalie Boddaert, Marie Gonzales, Marie Alice Macher, Hubert Nivet, Gérard Champion, Jean Pierre Berthélémé, Patrick Niaudet, Fiona McDonald, Friedhelm Hildebrandt, Colin A. Johnson, Michel Vekemans, Corinne Antignac, Ulrich Rüther, Sylvie Schneider-Maunoury, Tania Attié-Bitach, Sophie Saunier

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391 Scopus citations

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.

Original language	English (US)
Pages (from-to)	875-881
Number of pages	7
Journal	Nature genetics
Volume	39
Issue number	7
DOIs	https://doi.org/10.1038/ng2039
State	Published - Jul 2007

ASJC Scopus subject areas

Genetics

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Delous, M., Baala, L., Salomon, R., Laclef, C., Vierkotten, J., Tory, K., Golzio, C., Lacoste, T., Besse, L., Ozilou, C., Moutkine, I., Hellman, N. E., Anselme, I., Silbermann, F., Vesque, C., Gerhardt, C., Rattenberry, E., Wolf, M. T. F., Gubler, M. C., ... Saunier, S. (2007). The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nature genetics, 39(7), 875-881. https://doi.org/10.1038/ng2039

Delous, M, Baala, L, Salomon, R, Laclef, C, Vierkotten, J, Tory, K, Golzio, C, Lacoste, T, Besse, L, Ozilou, C, Moutkine, I, Hellman, NE, Anselme, I, Silbermann, F, Vesque, C, Gerhardt, C, Rattenberry, E, Wolf, MTF, Gubler, MC, Martinovic, J, Encha-Razavi, F, Boddaert, N, Gonzales, M, Macher, MA, Nivet, H, Champion, G, Berthélémé, JP, Niaudet, P, McDonald, F, Hildebrandt, F, Johnson, CA, Vekemans, M, Antignac, C, Rüther, U, Schneider-Maunoury, S, Attié-Bitach, T & Saunier, S 2007, 'The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome', Nature genetics, vol. 39, no. 7, pp. 875-881. https://doi.org/10.1038/ng2039

@article{6c69d4d6a416496d96d2270d614bab1d,

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

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.",

author = "Marion Delous and Lekbir Baala and R{\'e}mi Salomon and Christine Laclef and Jeanette Vierkotten and K{\`a}lm{\`a}n Tory and Christelle Golzio and Tiphanie Lacoste and Laurianne Besse and Catherine Ozilou and Imane Moutkine and Hellman, {Nathan E.} and Isabelle Anselme and Flora Silbermann and Christine Vesque and Christoph Gerhardt and Eleanor Rattenberry and Wolf, {Matthias T F} and Gubler, {Marie Claire} and J{\'e}l{\'e}na Martinovic and F{\'e}r{\'e}cht{\'e} Encha-Razavi and Nathalie Boddaert and Marie Gonzales and Macher, {Marie Alice} and Hubert Nivet and G{\'e}rard Champion and Berth{\'e}l{\'e}m{\'e}, {Jean Pierre} and Patrick Niaudet and Fiona McDonald and Friedhelm Hildebrandt and Johnson, {Colin A.} and Michel Vekemans and Corinne Antignac and Ulrich R{\"u}ther and Sylvie Schneider-Maunoury and Tania Atti{\'e}-Bitach and Sophie Saunier",

note = "Funding Information: 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{\textquoteright}Orthog{\'e}nie at the Broussais hospital in Paris for their contributions. This work was supported by grants from GIS-Maladies Rares (AAE05017KSA), the Association pour l{\textquoteright}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 Minist{\`e}re de la Recherche, K.T. and N.E.H. were supported from a grant from the Fondation Recherche M{\'e}dicale, 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).",

year = "2007",

month = jul,

doi = "10.1038/ng2039",

language = "English (US)",

volume = "39",

pages = "875--881",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

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TY - JOUR

T1 - The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

AU - Delous, Marion

AU - Baala, Lekbir

AU - Salomon, Rémi

AU - Laclef, Christine

AU - Vierkotten, Jeanette

AU - Tory, Kàlmàn

AU - Golzio, Christelle

AU - Lacoste, Tiphanie

AU - Besse, Laurianne

AU - Ozilou, Catherine

AU - Moutkine, Imane

AU - Hellman, Nathan E.

AU - Anselme, Isabelle

AU - Silbermann, Flora

AU - Vesque, Christine

AU - Gerhardt, Christoph

AU - Rattenberry, Eleanor

AU - Wolf, Matthias T F

AU - Gubler, Marie Claire

AU - Martinovic, Jéléna

AU - Encha-Razavi, Féréchté

AU - Boddaert, Nathalie

AU - Gonzales, Marie

AU - Macher, Marie Alice

AU - Nivet, Hubert

AU - Champion, Gérard

AU - Berthélémé, Jean Pierre

AU - Niaudet, Patrick

AU - McDonald, Fiona

AU - Hildebrandt, Friedhelm

AU - Johnson, Colin A.

AU - Vekemans, Michel

AU - Antignac, Corinne

AU - Rüther, Ulrich

AU - Schneider-Maunoury, Sylvie

AU - Attié-Bitach, Tania

AU - Saunier, Sophie

N1 - Funding Information: 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).

PY - 2007/7

Y1 - 2007/7

N2 - 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.

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

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