The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy
The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy
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DOI：
10.1093/hmg/ddm248
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发表时间：
2007-12-01
影响因子：
3.5
通讯作者：
Escayg, Andrew
中科院分区：
文献类型：
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作者：
Martin, Melinda S.;Tang, Bin;Escayg, Andrew
哺乳动物基因组包含四种电压门控钠通道基因，主要在中枢神经系统中表达：SCN1A、SCN2A、SCN3A 和 SCN8A。 SCN1A 和 SCN2A 突变导致多种显性特发性癫痫疾病，包括全身性癫痫伴热性惊厥附加症 (GEFS+) 和严重婴儿肌阵挛性癫痫 (SMEI)。 SCN8A 突变与人类的认知缺陷和神经精神疾病以及小鼠的运动障碍有关；然而，SCN8A (Na(v)1.6) 在癫痫中的作用尚未得到研究。为了确定 Nav1.6 功能障碍和癫痫易感性之间的关系，我们检查了两种 Scn8a 小鼠突变体 Scn8a(med) 和 Scn8a (med-jo) 对氟草酸和红藻氨酸 (KA) 诱导的癫痫发作的阈值。两种突变体都比野生型同窝小鼠更能抵抗癫痫发作，这表明 Nav1.6 功能的改变降低了神经元的兴奋性。为了确定 Nav1.6 功能受损是否可以改善 SMEI 小鼠模型中癫痫发作的严重程度，我们生成了 Scn1a(+/-)； Scn8a (med-jo/+) 双杂合小鼠。与更容易受到氟草酯诱导的癫痫发作的 Scn1a(+/-) 小鼠不同，Scn1a(+/-); Scn8a(med-jo/+) 小鼠表现出与野生型同窝小鼠相当的阈值。 Scn8a(med-jo)等位基因还能够挽救Scn1a(+/-)小鼠的过早死亡并延长Scn1a(-/-)突变体的寿命。这些结果表明，遗传相互作用可以改变癫痫发作的严重程度，并支持遗传修饰因素导致 SMEI 和 GEFS+ 中观察到的临床变异性的假设。
The mammalian genome contains four voltage-gated sodium channel genes that are primarily expressed in the central nervous system: SCN1A, SCN2A, SCN3A and SCN8A. Mutations in SCN1A and SCN2A are responsible for several dominant idiopathic epilepsy disorders, including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). Mutations in SCN8A are associated with cognitive deficits and neuropsychiatric illness in humans and movement disorders in mice; however, a role for SCN8A (Na(v)1.6) in epilepsy has not been investigated. To determine the relationship between Nav1.6 dysfunction and seizure susceptibility, we examined the thresholds of two Scn8a mouse mutants, Scn8a(med) and Scn8a (med-jo), to flurothyl- and kainic acid (KA)-induced seizures. Both mutants were more seizure resistant than wild-type littermates, suggesting that altered Nav1.6 function reduces neuronal excitability. To determine whether impaired Nav1.6 function could ameliorate seizure severity in a mouse model of SMEI, we generated Scn1a(+/-); Scn8a (med-jo/+) double heterozygous mice. Unlike Scn1a(+/-) mice that are more susceptible to flurothyl- induced seizures, Scn1a(+/-); Scn8a(med-jo/+) mice displayed thresholds that were comparable to wildtype littermates. The Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a(+/-) mice and extend the lifespan of Scn1a(-/-) mutants. These results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in SMEI and GEFS+.