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

Autor:	Thomas S; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France., Cantagrel V; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA., Mariani L; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Serre V; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] UMR7592CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France., Lee JE; Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA., Elkhartoufi N; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., de Lonlay P; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Desguerre I; Service de neurométabolisme, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Munnich A; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Boddaert N; Radiologie Pédiatrique et INSERM U-797, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Lyonnet S; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Vekemans M; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Lisgo SN; The MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle Upon Tyne, UK., Caspary T; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA., Gleeson J; Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA., Attié-Bitach T; 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France [3] Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Jazyk:	angličtina
Zdroj:	European journal of human genetics : EJHG [Eur J Hum Genet] 2015 May; Vol. 23 (5), pp. 621-7. Date of Electronic Publication: 2014 Aug 20.
DOI:	10.1038/ejhg.2014.156
Abstrakt:	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.
Databáze:	MEDLINE
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