Functional consequences of SLC1A3 mutations associated with episodic ataxia 6.,Human Mutation

当前位置： X-MOL 学术 › Hum. Mutat. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Functional consequences of SLC1A3 mutations associated with episodic ataxia 6.
Human Mutation ( IF 3.3 ) Pub Date : 2020-08-02 , DOI: 10.1002/humu.24089
Aparna S Chivukula ₁ , Mariia Suslova ₁ , Daniel Kortzak ₁ , Peter Kovermann ₁ , Christoph Fahlke ₁

Affiliation

The episodic ataxias (EA) are a group of inherited neurological diseases characterized by paroxysmal cerebellar incoordination. There exist nine forms of episodic ataxia with distinct neurological symptoms and genetic origins. Episodic ataxia type 6 (EA6) differs from other EA forms in long attack duration, epilepsy and absent myokymia, nystagmus, and tinnitus. It has been described in seven families, and mutations in SLC1A3, the gene encoding the glial glutamate transporter EAAT1, were reported in each family. How these mutations affect EAAT1 expression, subcellular localization, and function, and how such alterations result in the complex neurological phenotype of EA6 is insufficiently understood. We here compare the functional consequences of all currently known mutations by heterologous expression in mammalian cells, biochemistry, confocal imaging, and whole‐cell patch clamp recordings of EAAT1 transport and anion currents. We observed impairments of multiple EAAT1 properties ranging from changes in transport function, impaired trafficking to increased protein expression. Many mutations caused only slight changes illustrating how sensitively the cerebellum reacts on impaired EAAT1 functions.

中文翻译：

与发作性共济失调相关的 SLC1A3 突变的功能后果 6.

发作性共济失调 (EA) 是一组以阵发性小脑不协调为特征的遗传性神经系统疾病。有九种形式的发作性共济失调，具有不同的神经症状和遗传起源。发作性共济失调 6 型 (EA6) 与其他 EA 形式的不同之处在于发作持续时间长、癫痫和无肌痉挛、眼球震颤和耳鸣。它已在七个家族中被描述，并在SLC1A3 中发生突变，编码神经胶质谷氨酸转运蛋白 EAAT1 的基因，在每个家族中都有报道。这些突变如何影响 EAAT1 表达、亚细胞定位和功能，以及这些改变如何导致 EA6 复杂的神经学表型尚不清楚。我们在这里通过哺乳动物细胞中的异源表达、生物化学、共聚焦成像和全细胞膜片钳记录 EAAT1 转运和阴离子电流来比较所有当前已知突变的功能后果。我们观察到多种 EAAT1 特性的损害，从运输功能的变化、运输受损到蛋白质表达增加。许多突变只引起轻微的变化，说明小脑对受损的 EAAT1 功能的反应有多敏感。

更新日期：2020-08-02

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11