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

Lookup NU author(s): Dr Steven LisgoORCiD


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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.

Publication metadata

Author(s): Thomas S, Cantagrel V, Mariani L, Serre V, Lee JE, Elkhartoufi N, de Lonlay P, Desguerre I, Munnich A, Boddaert N, Lyonnet S, Vekemans M, Lisgo SN, Caspary T, Gleeson J, Attie-Bitach T

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2015

Volume: 23

Issue: 5

Pages: 621-627

Print publication date: 01/05/2015

Online publication date: 20/08/2014

Acceptance date: 09/07/2014

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Nature Publishing Group


DOI: 10.1038/ejhg.2014.156


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