Early-onset familial hemiplegic migraine due to a novel SCN1A mutation
Early-onset familial hemiplegic migraine due to a novel SCN1A mutation
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DOI：
10.1177/0333102415608360
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发表时间：
2016-11-01
期刊：
影响因子：
4.9
通讯作者：
Jurkat-Rott, Karin
中科院分区：
文献类型：
--
作者：
Fan, Chunxiang;Wolking, Stefan;Jurkat-Rott, Karin
家族性偏瘫型偏头痛是一种罕见的常染色体显性遗传的有先兆偏头痛亚型。FHM 3亚型是由SCN 1A突变引起的，SCN 1A也是编码电压门控Na+通道Na（V）1.1的最常见癫痫基因。本研究的目的是探讨一个FHM 3纯系家系的临床、遗传和发病特点。全细胞膜片钳，以确定确定的突变Na（V）1.1通道，这是瞬时表达在人类tsA201细胞连同（1）和（2）subunits.Results和conclusions的功能，我们确定了一种新的SCN1A（p.Leu1624Pro）突变的纯FHM家族中，显着早发性发作，平均年龄为7。L1624 P位于结构域IV的S3，与四个已知的纯FHM 3突变中的两个相同。与WT通道相比，L1624 P显示出增加的阈值附近持续电流以及其他功能获得性特征，例如：快速失活的减缓、稳态失活的正向转变、更快的恢复和重复刺激期间更高的通道可用性。类似于已知的FHM 3突变，这种新的突变预测GABA能抑制性神经元的超兴奋性。
Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel Na(V)1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family.Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant Na(V)1.1 channels, which were transiently expressed in human tsA201 cells together with (1) and (2) subunits.Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.