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

被引:375
作者
Delous, Marion
Baala, Lekbir
Salomon, Remi
Laclef, Christine
Vierkotten, Jeanette
Tory, Kalman
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, Jelena
Encha-Razavi, Ferechte
Boddaert, Nathalie
Gonzales, Marie
Macher, Marie Alice
Nivet, Hubert
Champion, Gerard
Bertheleme, Jean Pierre
Niaudet, Patrick
McDonald, Fiona
Hildebrandt, Friedhelm
Johnson, Colin A.
Vekemans, Michel
Antignac, Corinne
Ruether, Ulrich
Schneider-Maunoury, Sylvie
Attie-Bitach, Tania
Saunier, Sophie [1 ]
机构
[1] INSERM, Hop Necker Enfants Malad, U574, F-75015 Paris, France
[2] Univ Paris 05, F-75006 Paris, France
[3] Hop Necker Enfants Malad, INSERM, U781, F-75015 Paris, France
[4] Hop Necker Enfants Malad, APHP, F-75015 Paris, France
[5] CNRS, UMR7622, Dev Biol Lab, F-75005 Paris, France
[6] Univ Paris 06, F-75005 Paris, France
[7] Univ Dusseldorf, Inst Entwicklungs & Mol Biol Tiere, EMT, D-40225 Dusseldorf, Germany
[8] Hop Necker Enfants Malad, APHP, Dept Genet, F-75015 Paris, France
[9] Womens Hosp Med Ctr, W Midlands Reg Genet, Birmingham B15 2TG, W Midlands, England
[10] Univ Michigan, Dept Pediat & Human Genet, Ann Arbor, MI 48109 USA
[11] Hop Necker Enfants Malad, F-75015 Paris, France
[12] Hop Trousseau, Dept Foetopathol, F-75012 Paris, France
[13] Hop Robert Debre, APHP, Dept Pediat, F-75019 Paris, France
[14] CHU Bretonneau, Dept Nephrol & Clin Immunol, F-37000 Tours, France
[15] CHU Angers, Dept Pediat Nephrol, F-49100 Angers, France
[16] Ctr Perharidy, F-29680 Roscoff, France
[17] St James Univ Hosp, Leeds Inst Mol Med, Sect Ophthalmol & Neurosci, Leeds LS9 7TF, W Yorkshire, England
关键词
D O I
10.1038/ng2039
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:875 / 881
页数:7
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