Episodic ataxia type 1 (EA1) is a human dominant neurological syndrome characterized by continuous myokymia, episodic attacks of ataxic gait and spastic contractions of skeletal muscles that can be triggered by emotional stress and fatigue. This rare disease is caused by missense mutations in the KCNA1 gene coding for the neuronal voltage gated potassium channel Kv1.1, which contributes to nerve cell excitability in the cerebellum, hippocampus, cortex and peripheral nervous system. We identified a novel KCNA1 mutation, E283K, in an Italian proband presenting with paroxysmal ataxia and myokymia aggravated by painful contractures and metabolic dysfunctions. The E283K mutation is located in the S3-S4 extracellular linker belonging to the voltage sensor domain of Kv channels. In order to test whether the E283K mutation affects Kv1.1 biophysical properties we transfected HEK293 cells with WT or mutant cDNAs alone or in a 1:1 combination, and recorded relative potassium currents in the whole-cell configuration of patch-clamp. Mutant E283K channels display voltage-dependent activation shifted by 10mV toward positive potentials and kinetics of activation slowed by ~2 fold compared to WT channels. Potassium currents resulting from heteromeric WT/E283K channels show voltage-dependent gating and kinetics of activation intermediate between WT and mutant homomeric channels. Based on homology modeling studies of the mutant E283K, we propose a molecular explanation for the reduced voltage sensitivity and slow channel opening. Overall, our results suggest that the replacement of a negatively charged residue with a positively charged lysine at position 283 in Kv1.1 causes a drop of potassium current that likely accounts for EA-1 symptoms in the heterozygous carrier.

中文翻译：

---

患有阵发性共济失调，肌强直，疼痛性挛缩和代谢功能异常的患者的新型KCNA1突变。

发作性共济失调1型（EA1）是一种人类占主导地位的神经系统综合症，其特征在于持续的肌强直，共济失调步态的发作性发作和骨骼肌的痉挛性收缩（可能由情绪压力和疲劳引起）。这种罕见的疾病是由编码神经元电压门控钾通道Kv1.1的KCNA1基因的错义突变引起的，该突变有助于小脑，海马，皮层和周围神经系统的神经细胞兴奋性。我们在意大利先证者中发现了一个新的KCNA1突变E283K，该突变表现为阵发性共济失调和肌强直，疼痛性挛缩和代谢功能障碍加重了病情。E283K突变位于S3-S4细胞外接头中，属于Kv通道的电压传感器域。为了测试E283K突变是否影响Kv1。1生物物理特性我们单独或以1：1组合用WT或突变cDNA转染HEK293细胞，并在膜片钳的全细胞配置中记录相对钾电流。与WT通道相比，突变的E283K通道显示出电压依赖性激活向正电位偏移10mV，激活动力学减慢了约2倍。异源WT / E283K通道产生的钾电流显示出电压依赖性门控和WT与突变同源通道之间的活化中间体动力学。基于突变体E283K的同源性建模研究，我们提出了降低电压敏感性和缓慢通道打开的分子解释。总体而言，我们的结果表明，在Kv1的位置283处，用带正电的赖氨酸代替了带负电的残基。