title: A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.
abstract: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].
authors: Center for Integrative Genomics (CIG), University of Lausanne, Switzerland.
authors: Hyun
authors: H
authors: Hor
authors: Luca
authors: L
authors: Bartesaghi
authors: Zoltán
authors: Z
authors: Kutalik
authors: José L
authors: JL
authors: Vicário
authors: Clara
authors: C
authors: de Andrés
authors: Corinne
authors: C
authors: Pfister
authors: Gert J
authors: GJ
authors: Lammers
authors: Nicolas
authors: N
authors: Guex
authors: Roman
authors: R
authors: Chrast
authors: Mehdi
authors: M
authors: Tafti
authors: Rosa
authors: R
authors: Peraita-Adrados
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008126:Lod Score; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009290:Narcolepsy / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D013030:Spain
chemical_list: C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein