A novel mutation in SLC1A3 causes episodic ataxia
A novel mutation in SLC1A3 causes episodic ataxia
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DOI：
10.1038/s10038-017-0365-z
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发表时间：
2018-02-01
影响因子：
3.5
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Iwama, Kazuhiro;Iwata, Aya;Matsumoto, Naomichi
发作性共济失调(EAs)是一种罕见的以反复共济失调和眩晕为特征的通道病，分为八个亚型。在这8个亚型中的4个(EA1、EA2、EA5和EA6)中发现了突变基因。到目前为止，只有溶质携带者家族1成员3基因(SLC1A3)的四个错义突变被报道导致EA6。SLC1A3编码兴奋性氨基酸转运蛋白1，是一种负责突触间隙谷氨酸转运的三聚体跨膜蛋白。在这项研究中，我们通过全外显子测序在一例EA患者中发现了一个新的错义突变，c.383T>；G(p.Met128Arg)。模型结构分析表明，p.Met128Arg可能影响疏水的跨膜环境和蛋白质功能。使用多种预测工具对迄今为止在SLC1A3中发现的所有突变的致病性进行分析表明，使用孟德尔临床适用致病性(M-CAP)评分具有一定的优势。Exac数据库中各种类型的SLC1A3变异，包括无义突变和Indels，表明SLC1A3突变导致的功能丧失机制在EA6中不太可能发生。目前的突变(p.Med128Arg)可能具有先前报告中描述的功能获得效应。
Episodic ataxias (EAs) are rare channelopathies characterized by recurrent ataxia and vertigo, having eight subtypes. Mutated genes were found in four of these eight subtypes (EA1, EA2, EA5, and EA6). To date, only four missense mutations in the Solute Carrier Family 1 Member 3 gene (SLC1A3) have been reported to cause EA6. SLC1A3 encodes excitatory amino-acid transporter 1, which is a trimeric transmembrane protein responsible for glutamate transport in the synaptic cleft. In this study, we found a novel missense mutation, c. 383T>G (p. Met128Arg) in SLC1A3, in an EA patient by whole-exome sequencing. The modeled structural analysis suggested that p. Met128Arg may affect the hydrophobic transmembrane environment and protein function. Analysis of the pathogenicity of all mutations found in SLC1A3 to date using multiple prediction tools showed some advantage of using the Mendelian Clinically Applicable Pathogenicity (M-CAP) score. Various types of SLC1A3 variants, including nonsense mutations and indels, in the ExAC database suggest that the loss-of-function mechanism by SLC1A3 mutations is unlikely in EA6. The current mutation (p. Med128Arg) presumably has a gain-of-function effect as described in a previous report.