Gain of Function for the SCN1A/hNa(v)1.1-L1670W Mutation Responsible for Familial Hemiplegic Migraine.
Gain of Function for the SCN1A/hNa(v)1.1-L1670W Mutation Responsible for Familial Hemiplegic Migraine.
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DOI：
10.3389/fnmol.2018.00232
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发表时间：
2018
影响因子：
4.8
通讯作者：
Cestèle S
中科院分区：
文献类型：
--
作者：
Dhifallah S;Lancaster E;Merrill S;Leroudier N;Mantegazza M;Cestèle S
SCN1A基因编码电压依赖的Nav1.1 Na+通道，这是一种主要在GABA能神经元中表达的异构体，是数百种致痫突变的目标。最近，有研究表明，SCN1A基因也是导致家族性偏瘫偏头痛(FHM-3)的突变的靶点，FHM-3是一种罕见的常染色体显性先兆偏头痛亚型。对这些突变的研究表明，它们导致了通道功能的增强。令人惊讶的是，导致纯FHM-3的突变L1649Q显示出完全的功能丧失，但当部分挽救它时，由于突变通道的门控属性的改变，导致了整体功能的获得。在这里，我们报告了L1670W SCN1A突变的特征，该突变以前在一个纯FHM-3的中国家庭中被发现，我们也在一个纯FHM-3的高加索美国家庭中发现。值得注意的是，我们家族中的一名患者在接受脑部放射治疗癌症后出现了严重的神经恶化。对L1670W的功能分析表明，突变是导致折叠/运输缺陷的原因，当它们通过低温孵育或在神经元中表达而被拯救时，门控属性的改变会导致整体功能的获得。因此，L1670W是导致FHM-3的第二个突变，具有这种病理生理机制，表明它可能是Nav1.1偏瘫偏头痛突变的复发机制。
The SCN1A gene encodes for the voltage-dependent Nav1.1 Na+ channel, an isoform mainly expressed in GABAergic neurons that is the target of hundreds of epileptogenic mutations. More recently, it has been shown that the SCN1A gene is also the target of mutations responsible for familial hemiplegic migraine (FHM-3), a rare autosomal dominant subtype of migraine with aura. Studies of these mutations indicate that they induce gain of function of the channel. Surprisingly, the mutation L1649Q responsible for pure FHM-3 showed a complete loss of function, but, when partially rescued it induced an overall gain of function because of modification of the gating properties of the mutant channel. Here, we report the characterization of the L1670W SCN1A mutation that has been previously identified in a Chinese family with pure FHM-3, and that we have identified also in a Caucasian American family with pure FHM-3. Notably, one patient in our family had severe neurological deterioration after brain radiation for cancer treatment. Functional analysis of L1670W reveals that the mutation is responsible for folding/trafficking defects and, when they are rescued by incubation at lower temperature or by expression in neurons, modifications of the gating properties lead to an overall gain of function. Therefore, L1670W is the second mutation responsible for FHM-3 with this pathophysiological mechanism, showing that it may be a recurrent mechanism for Nav1.1 hemiplegic migraine mutations.
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