The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome

Baala, Lekbir; Romano, S.; Khaddour, Rana; Saunier, Sophie; Smith, Ursula M; Audollent, Sophie; Ozilou, Catherine; Faivre, Laurence; Laurent, Nicole; Foliguet, B; Münnich, Arnold; Lyonnet, Stanislas; Salomon, Rémi; Encha‐Razavi, Férechté; Gubler, Marie–Claire; Boddaert, Nathalie; Lonlay, Pascale de; Johnson, Colin A.; Vekemans, Michel; Antignac, Corinne; Attié‐Bitach, Tania

doi:10.1086/510499

Cited by 212 publications

(180 citation statements)

References 51 publications

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“…Thus, one may hypothesize a putative phenotype-genotype correlation with respect to the mutated MKS gene. This is in line with data from Baala et al [2007] who also observed the classic MKS phenotype with occipital meningoencephalocele in MKS1-mutated foetuses, whereas MKS3-mutated patients more often presented with a Dandy-Walker malformation and lack of postaxial polydactyly.…”

Section: Mks1 Is a Major Mks Locus And Not Restricted To Caucasianssupporting

confidence: 91%

Aberrant splicing is a common mutational mechanism inMKS1, a key player in Meckel-Gruber syndrome

et al. 2007

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Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS.

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Section: Mks1 Is a Major Mks Locus And Not Restricted To Caucasianssupporting

confidence: 91%

Aberrant splicing is a common mutational mechanism inMKS1, a key player in Meckel-Gruber syndrome

et al. 2007

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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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“…Mutations in TMEM67 ( MKS3 ) are responsible for the majority of COACH syndrome, although mutations in CC2D2A and RPGRIP1L can also be causative 78, 9, 10, 11. Although mutations in TMEM67/MKS3 are causative for both syndromes (accounting for 9% of JSRD cases and 16% of MKS cases), a correlation between missense mutations in exons 8‐15, particularly in combination with truncating mutations, and Meckel‐Gruber syndrome has been identified 7, 12…”

Section: Introductionmentioning

confidence: 99%