Both gain-and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.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.

前庭性偏头痛相关基因的研究进展

前庭偏头痛(VM)是一种急性前庭综合征,被认为是复发性眩晕最常见的原因之一,眩晕发作时可能出现自发性或体位性眩晕、视觉引起的眩晕及视物模糊等临床表现,其主要诊断依据是偏头痛发作期间的病史和偏头痛症状。越来越多的研究表明,影响VM的主要因素就是基因变异,目前偏头痛的相关基因尚在研究中,具体有多少种相关性基因尚不明确,本文的目的是研读偏头痛相关基因的文献并予以综述。

在癫痫猝死模型中昼夜节律改变和时钟基因及Sirtuin 1的振荡

许多神经系统疾病都会影响昼夜节律。尽管已知癫痫常伴睡眠障碍,但与癫痫昼夜节律紊乱相关的数据却很少。文章检验了Kcna1缺失小鼠的昼夜休息活动以及睡眠-觉醒模式。该小鼠模型表现出反复自发癫痫发作,也是研究癫痫猝死的模型。此外,研究试图确定癫痫发作以及核心时钟基因和调节因子Sirtuin 1(Sirt1)的异常变化是否与昼夜节律紊乱有关。研究使用被动红外活动记录仪评估休息活动模式,使用脑电图(EEG)进行癫痫发作和睡眠分析,并且使用逆转录聚合酶链反应和蛋白质印迹法评估时钟基因和Sirt1在Kcna1缺失和野生型小鼠中的表达情况。癫痫Kcna1缺失动物模型存在昼夜休息活动模式紊乱,趋于表现出延长的昼夜节律。EEG分析证实了睡眠结构的破坏,清醒时间更多并且睡眠不足。尽管所有癫痫小鼠都表现出昼夜休息活动模式的紊乱,但该研究发现实际癫痫发作负担与睡眠紊乱程度之间没有相关性。发现前下丘脑中几个时钟基因(即Clock,Bmal1,Per1和Per2)和昼间Sirt1 mRNA的衰减振荡。几个核心时钟基因的振荡衰减与Kcna1缺失小鼠中观察到的异常昼夜休息活动以及睡眠-觉醒模式改变相关,可能是其基础原因,并可能导致癫痫晚期并发症,例如癫痫猝死。Sirt1可能是恢复生物钟基因节律和癫痫睡眠模式的潜在治疗靶点之一。