Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.
Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.
复制标题
家族性孤立性肌阵挛中钠通道 SCN8A 部分功能丧失。
DOI：
10.1002/humu.23547
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发表时间：
2018
期刊：
影响因子：
3.9
通讯作者：
Meisler,MiriamH
中科院分区：
文献类型：
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作者：
Wagnon,JacyL;Mencacci,NiccolòE;Barker,BryanS;Wengert,EricR;Bhatia,KailashP;Balint,Bettina;Carecchio,Miryam;Wood,NicholasW;Patel,ManojK;Meisler,MiriamH
神经元钠通道基因SCN 8A的变异体与几种神经系统疾病有关。早期婴儿癫痫性脑病13型是由改变通道生物物理特性的从头获得功能突变引起的。在孤立性智力残疾的病例中，已确定了SCN 8A的功能完全丧失变体。我们现在报告了一个新的异源性SCN 8 A变异体，p.Pro1719Arg，在一个小的家系中，有5个家族成员患有常染色体显性遗传的上肢孤立性肌阵挛，没有癫痫发作或认知功能障碍。在转染的神经元衍生细胞中对p.Pro1719Arg变体的功能分析表明，Nav1.6通道活性大大降低，而门控特性没有改变。已知小鼠中Scn 8的亚型等位基因导致类似的运动障碍。本研究扩展了SCN 8A变异体的表型和功能谱，包括遗传性非癫痫性孤立性肌阵挛，SCN 8A可被认为是无癫痫发作的孤立性运动障碍的候选基因。
Variants in the neuronal sodium channel geneSCN8Ahave been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain‐of‐function mutations that alter the biophysical properties of the channel. Complete loss‐of‐function variants ofSCN8Ahave been identified in cases of isolated intellectual disability. We now report a novel heterozygousSCN8Avariant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron‐derived cells demonstrated greatly reduced Nav1.6 channel activity without altered gating properties. Hypomorphic alleles ofScn8ain the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum ofSCN8Avariants to include inherited nonepileptic isolated myoclonus.SCN8Acan be considered as a candidate gene for isolated movement disorders without seizures.