论文标题
TMEM240突变引起脊椎动物共济失调21，具有智力低下和严重的认知障碍
TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment
论文作者
论文摘要
常染色体显性小脑共济失调对应于主要影响小脑的临床和遗传异质性神经退行性疾病。在这里，我们报告了脊髓脑性共济失调21中的致病基因的鉴定，这是一种常染色体降低的疾病，以前映射到7p21.3-p15.1染色体。这种共济失调首先是在一个大型法国家庭中，具有缓慢的小脑共济失调，并伴有两个年幼的孩子的严重认知障碍和智力低下。在招募了12名年轻家庭成员之后，连锁分析使我们能够将疾病基因座定义为1p36.33-p36.32染色体。通过整个外显子组测序鉴定了跨膜蛋白基因TMEM240中的致病突变（C.509C4T/P.P170L），然后通过Sanger测序和共隔离分析确认。还筛选了来自368个法国常染色性小脑共济失调的法国家庭的指数病例以进行突变。在七个情况下，我们确定了一系列错义突变（C.509C4T/P.P170L，C.239C4T/P.T80M，C.346C4T/P.R116C，C.445G4A/P.E149K，C.511C4T/P.R171W），以及一个c.4889c43163*ine in in c.489c43.y1。 TMEM240是一种小脑和大脑中存在的不明功能的较小，坚固的跨膜蛋白。脊髓脑性共济失调21可能是一种与严重认知障碍有关的特定早期疾病。
Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C4T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C4T/p.P170L, c.239C4T/p.T80M, c.346C4T/p.R116C, c.445G4A/p.E149K, c.511C4T/p.R171W), and a stop mutation (c.489C4G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.
