Center for Integrative Genomics (CIG), University of Lausanne, Switzerland.
Am J Hum Genet. 2011 Sep 9;89(3):474-9. doi: 10.1016/j.ajhg.2011.08.007.
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].
发作性睡病是一种罕见的睡眠障碍，其特征是白天过度嗜睡和猝倒。家族性发作性睡病占所有发作性睡病病例的不到 10%。然而，有记载的多发性家族非常罕见，迄今为止尚未发现致病突变。为了在家族性发作性睡病中鉴定出致病突变，我们对迄今为止报道的最大家族进行了连锁分析，该家族有 12 名受影响的成员，并对 3 名患有发作性睡病和猝倒的受影响成员的基因组编码区域（外显子组测序）进行了测序。我们通过连锁分析成功地在染色体 6p22.1 区域定位了一个候选基因座（LOD 得分¼3.85）。外显子组测序在连锁区域内的 MO G 第二外显子中鉴定出一个错义突变。c.398C>G 突变存在于所有受影响的家族成员中，但不存在于未受影响的成员和 775 名无关对照中。突变型髓鞘少突胶质细胞糖蛋白（MO G）在小鼠少突胶质细胞中的瞬时表达显示异常的亚细胞定位，表明突变 MO G 的功能发生改变。MO G 最近与多种神经精神疾病有关，被认为是多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎中的关键自身抗原。我们发现致病性 MO G 突变突出了髓鞘和少突胶质细胞在发作性睡病中的主要作用，并进一步强调了神经胶质细胞在神经退行性变和神经行为障碍中的参与。[更正]。
