title: Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity.
abstract: 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.
authors.affiliation: 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Mariani
authors.affiliation: 1] INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France [2] UMR7592CNRS, Jacques Monod Institute, Paris Diderot University, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.affiliation: Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhartoufi
authors.affiliation: 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.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: Service de neurométabolisme, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: 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.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Radiologie Pédiatrique et INSERM U-797, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: 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.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.affiliation: The MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle Upon Tyne, UK.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Lisgo
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Caspary
authors.affiliation: Laboratory of Neurogenetics, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gleeson
authors.affiliation: 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.
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D020727:ADP-Ribosylation Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000473:pathology; D002526:Cerebellar Diseases / Q000175:diagnosis* / Q000235:genetics*; D019295:Computational Biology; D003241:Consanguinity; D004195:Disease Models, Animal; D015785:Eye Diseases, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D012164:Retinal Diseases / Q000175:diagnosis / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015027:Zebrafish
chemical_list: D020727:ADP-Ribosylation Factors; C530391:ARL13B protein, human