Abstract：
KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channel α subunit. Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia (PKD), but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases. Using the whole exome sequencing followed by Sanger sequencing, we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families. The proband of one family (c.496G>A, p.A166T) manifests as episodic ataxia type 1, and the other two (c.877G>A, p.V293I and c.1112C>A, p.T371A) manifest as PKD. The pathogenicity of these variants is confirmed by functional studies, suggesting that p.A166T and p.T371A cause a loss-of-function of the channel, while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected. By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein, we find that these variants tend to cluster around the pore domain, which is similar to epilepsy. Thus, our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype-phenotype correlations of KCNA1 channelopathy.
摘要：
KCNA1是Kv1.1电压门控钾通道α亚基的编码基因。据报道，KCNA1的三种变体表现为阵发性运动障碍（PKD），但由于KCNA1变体的表型复杂性以及PKD病例的稀有性,它们之间的相关性尚不清楚.使用整个外显子组测序，然后进行Sanger测序，我们在临床诊断为阵发性运动障碍的患者中筛选了潜在的致病性KCNA1变异体,并在3个无关的中国家庭中鉴定了3个以前未报告的KCNA1错义变异体.一个家庭的先证者（c.496G>A，p.A166T）表现为1型发作性共济失调，另外两种表现为（c.877G>A，p.V293I;和c.1112C>A，p.T371A)显示为PKD。这些变异的致病性得到了功能研究的证实，表明p.A166T和p.T371A会导致通道功能丧失，而p.V293I导致功能增益，具有电压依赖性门控和激活动力学的特性。通过回顾PKD表现的KCNA1变体在Kv1.1蛋白中的位置，我们发现这些变体倾向于聚集在孔域周围，这与癫痫相似。因此，我们的研究加强了KCNA1变异体与PKD之间的相关性,并提供了有关KCNA1通道病基因型-表型相关性的更多信息.
