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

Delous, Marion; Baala, Lekbir; Salomon, Rémi; Laclef, Christine; Vierkotten, Jeanette; Tory, Kálmán; 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; Gubler, Marie–Claire; Martinovic, Jéléna; Encha‐Razavi, Férechté; Boddaert, Nathalie; Gonzalès, Marie; Macher, Marie Alice; Nivet, Hubert; Champion, G.; 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

doi:10.1038/ng2039

Cited by 446 publications

(515 citation statements)

References 26 publications

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“…19 This would be in line with the observation that mild mutations in MKS-associated genes can cause JBS, for example, RPGRIP1L/MKS5 and CC2D2A/MKS6. 35,36 The patient presented with a mild classic JBS phenotype without renal, retinal, or hepatic disease (at age 10 years), similar to the phenotype of two JBS cases with B9D1 mutations described recently. 19 The percentage of JBS cases with a heterozygous mutation in a known JBS gene (53%) is much higher than expected in a rare autosomal recessive disease (the estimated birth prevalence of JBS is 1 in 80 000 to 1 in 100 000); 2,7 however, we cannot exclude that a second pathogenic mutation is present but missed by our detection method.…”

Section: Non-mendelian Inheritance and B9d1supporting

confidence: 69%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

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Section: Non-mendelian Inheritance and B9d1supporting

confidence: 69%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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“…Despite two patients displaying an occipital encephalocele, no ARL13B variants have been found in Meckel syndrome fetuses (Cantagrel et al 9 and personal data), although Meckel syndrome has been shown to be the extreme lethal phenotype of JS for other genes. [29][30][31][32][33] In conclusion, we have identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient with retinal involvement and obesity. We have shown that this variant is hypomorphic, as it is unable to rescue efficiently either the arl13b sco zebrafish phenotype or the deficiencies in Arl13b hnn MEFs.…”

Section: Discussionmentioning

confidence: 67%

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

et al. 2014

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Joubert syndrome (JS) is a genetically heterogeneous autosomal recessive ciliopathy with 22 genes implicated to date, including a small, ciliary GTPase, ARL13B. ARL13B is required for cilia formation in vertebrates. JS patients display multiple symptoms characterized by ataxia due to the cerebellar vermis hypoplasia, and that can also include ocular abnormalities, renal cysts, liver fibrosis or polydactyly. These symptoms are shared with other ciliopathies, some of which display additional phenotypes, such as obesity. Here we identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient who displayed retinal defects and obesity. We demonstrate the variant disrupts ARL13B function, as its expression did not rescue the mutant phenotype either in Arl13b scorpion zebrafish or in Arl13b hennin mouse embryonic fibroblasts, while the wild-type ARL13B did. Finally, we show that ARL13B is localized within the primary cilia of neonatal mouse hypothalamic neurons consistent with the known link between hypothalamic ciliary function and obesity. Thus our data identify a novel ARL13B variant that causes JS and retinopathy and suggest an extension of the phenotypic spectrum of ARL13B mutations to obesity.

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“…These include Ableson-helper integration-1 (AHI1), Nephrocystin-1 (NPHP1), Centrosomal protein-290 (CEP290), Transmembrane protein 67 (TMEM67) and Retinitis pigmentosa GTPase regulator-interacting protein-like (RPGRIP1L). Each of the genes encodes a modular scaffolding protein without clear enzymatic domains, but sharing several protein-interaction domains of unknown function, suggesting that they may be part of a signaling complex [28][29][30][31][32][33][34][35][36] The Joubert syndrome connection with cilia Although the function of JSRD proteins remains largely unknown, recent evidence suggests roles in either mediating the assembly/stability of cilia or mediating cargo transport within cilia. When tested directly, at least three of the encoded proteins, NPHP1, CEP290 and RPGRIP1L have demonstrated localization to the basal body or cilium [32,[35][36][37], further suggesting a role at the cilium or basal body.…”

Section: Joubert Syndrome and Related Disordersmentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

171

141

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The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

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

Cited by 446 publications

References 26 publications

Joubert syndrome: genotyping a Northern European patient cohort

Joubert syndrome: genotyping a Northern European patient cohort

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

Cerebellar development and disease

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