Fan Chunxiang, Wolking Stefan, Lehmann-Horn Frank, Hedrich Ulrike Bs, Freilinger Tobias, Lerche Holger, Borck Guntram, Kubisch Christian, Jurkat-Rott Karin
1 Division of Neurophysiology, Ulm University, Germany.
2 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
Cephalalgia. 2016 Nov;36(13):1238-1247. doi: 10.1177/0333102415608360. Epub 2016 Jul 11.
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 Na1.1. 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 Na1.1 channels, which were transiently expressed in human tsA201 cells together with β and β 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.
引言
家族性偏瘫性偏头痛（FHM）是偏头痛伴先兆的一种罕见的常染色体显性亚型。FHM3亚型由SCN1A基因突变引起，SCN1A也是编码电压门控钠通道Na1.1的最常见癫痫基因。本研究的目的是探讨一个纯合FHM3家族的临床、遗传和发病机制特征。
方法
本研究纳入了一个三代家族进行基因检测和临床特征评估。采用全细胞膜片钳技术测定鉴定出的突变型Na1.1通道的功能，这些通道与β和β亚基一起在人tsA201细胞中瞬时表达。
结果与结论
我们在一个纯合FHM家族中鉴定出一种新的SCN1A（p.Leu1624Pro）突变，该家族平均发病年龄为7岁，发病较早。L1624P位于结构域IV的S3区，与四个已知的纯合FHM3突变中的两个位于同一结构域。与野生型通道相比，L1624P除了具有其他功能增强特征外，还表现出阈下近持续性电流增加，这些特征包括：快速失活减慢、稳态失活正向偏移、重复刺激期间恢复更快以及通道可用性更高。与已知的FHM3突变相似，这种新突变预示着GABA能抑制性神经元的兴奋性过高。
