Data_Sheet_1_Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I.DOCX

Episodic ataxia type 1 (EA1), a Shaker-like K+channelopathy, is a consequence of genetic anomalies in the KCNA1 gene that lead to dysfunctions in the voltage-gated K+ channel Kv1. 1. Generally, KCNA1 mutations are inherited in an autosomal dominant manner. Here we report the clinical phenotype of an EA1 patient characterized by ataxia attacks that decrease in frequency with age, and eventually leading to therapy discontinuation. A new de novo mutation (c.932G>A) that changed a highly conserved glycine residue into an aspartate (p.G311D) was identified by using targeted next-generation sequencing. The conserved glycine is located in the S4–S5 linker, a crucial domain controlling Kv1.1 channel gating. In silico analyses predicted the mutation deleterious. Heterologous expression of the mutant (Kv1.1-G311D) channels resulted in remarkably decreased amplitudes of measured current, confirming the identified variant is pathogenic. Collectively, these findings corroborate the notion that EA1 also results from de novo variants and point out that regardless of the mutation-induced deleterious loss of Kv1.1 channel function the ataxia phenotype may improve spontaneously.

发作性共济失调1型（Episodic ataxia type 1, EA1）作为一种类Shaker钾通道病，是由KCNA1基因遗传异常导致电压门控钾通道Kv1.1功能障碍所引发的疾病。通常情况下，KCNA1基因突变以常染色体显性方式遗传。本文报道1例EA1患者的临床表型：其共济失调发作频率随年龄增长逐渐降低，最终可停止治疗。通过靶向下一代测序（targeted next-generation sequencing），我们鉴定出1个新发突变（c.932G>A），该突变将高度保守的甘氨酸残基替换为天冬氨酸（p.G311D）。该保守甘氨酸位于S4-S5连接区——这是调控Kv1.1通道门控的关键结构域。计算机模拟分析（in silico analyses）预测该突变具有致病性。对突变体Kv1.1-G311D通道进行异源表达后，检测到的电流幅度显著降低，证实了该变异具有致病性。综上，本研究结果佐证了EA1亦可由新发变异导致，并提示无论基因突变通过何种有害方式造成Kv1.1通道功能丧失，其共济失调表型均可自发改善。