PDF(Pubmed)
Abstract：
Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.
摘要：
编码神经元电压门控钠通道的SCN1A基因的变异体NaV1.1导致超过85%的Dravet综合征病例。严重且通常为药物难治性癫痫性脑病，主要是婴儿发作。但是随着癫痫患者基因检测的普及，SCN1A的变异现在也被描述在一系列其他癫痫表型中.这些癫痫相关的变异绝大多数是从头的，大多数是截断通道的无义变体或被认为会导致通道功能丧失的错义变体。然而,生物物理分析揭示了导致兴奋性增加的错义突变的重要子集，SCN1A变异和癫痫患者的精确药物治疗方法进一步复杂化。我们描述了编码NaV1.1L1624Q突变体的家族性SCN1A变体的临床和生物物理数据。这种取代位于NaV1.1的结构域IV的S3和S4之间的细胞外连接子上，并且是家族性SCN1A变体引起常染色体显性遗传性额叶癫痫的罕见病例。我们在CHO细胞中表达野生型(WT)和L1642Q通道。使用膜片钳在几个温度下表征通道特性，我们表明L1624Q变体增加了持续电流，加速快速失活开始和降低电流密度。虽然SCN1A相关的癫痫通常被认为是一种功能丧失的疾病，我们的结果将L1624Q纳入了导致癫痫的SCN1A中越来越多的混合功能增益和功能丧失变异组.
