Molecular basis of an inherited epilepsy
Molecular basis of an inherited epilepsy
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DOI：
10.1016/s0896-6273(02)00714-6
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发表时间：
2002-06-13
期刊：
影响因子：
16.2
通讯作者：
George, AL
中科院分区：
文献类型：
--
作者：
Lossin, C;Wang, DW;George, AL
癫痫是一种常见的神经系统疾病，其反映的神经元高兴奋性主要源于尚不明确的细胞和分子机制。在伴有热性惊厥附加症的全面性癫痫（一种常染色体显性癫痫综合征）中，已确定编码电压门控钠通道α或β1亚基的三个基因（SCN1A、SCN2A、SCN1B）以及一个γ - 氨基丁酸（GABA）受体亚基基因（GABRG2）发生了突变。在此，我们通过在培养的哺乳动物细胞中使其与已知的辅助亚基β1和β2异源表达，来描述人类神经元钠通道α亚基SCN1A中三个突变的功能影响。SCN1A突变改变通道失活，导致持续性内向钠电流。这种功能获得性异常可能会通过引起细胞膜去极化延长而增强神经元膜的兴奋性，这是一种可能的导致这种遗传性人类癫痫的潜在生物物理机制。
Epilepsy is a common neurological condition that reflects neuronal hyperxcitability arising from largely unknown cellular and molecular mechanisms. In generalized epilepsy with febrile seizures plus, an autosomal dominant epilepsy syndrome, mutations in three genes coding for voltage-gated sodium channel a or beta1 subunits (SCN1A, SCN2A, SCN1B) and one GABA receptor subunit gene (GABRG2) have been identified. Here, we characterize the functional effects of three mutations in the human neuronal sodium channel a subunit SCN1A by heterologous expression with its known accessory subunits, beta1 and beta2, in cultured mammalian cells. SCN1A mutations alter channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality will likely enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for this inherited human epilepsy.