An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na+ current
An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na+ current
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DOI：
10.1111/epi.12241
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发表时间：
2013-09-01
期刊：
影响因子：
5.6
通讯作者：
Lesca, Gaetan
中科院分区：
文献类型：
--
作者：
Lauxmann, Stephan;Boutry-Kryza, Nadia;Lesca, Gaetan
编码脑钠通道NaV1.2的SCN 2A中的错义突变已在良性家族性脑-婴儿癫痫发作（BFNIS）（一种自限性疾病）中描述，而在具有更严重表型（包括癫痫性脑病）的患者中发现了几种SCN 2A从头无义突变。我们报告一个来自马达加斯加的BFNIS家族。发病年龄从3月龄延长至9月龄。发作间期脑电图正常。在两名患者中，发作期脑电图（EEG）研究显示部分癫痫发作模式，其中一人继发全身性发作。在18个月之前缓解的癫痫发作，有或没有药物治疗。智力发育正常。SCN 2A基因在NaV1.2高度保守区（D4/S2-S3）发现一个新的错义突变，即c.4766A>G/p.Tyr1589Cys。在tsA 201细胞和全细胞膜片钳中使用异源表达的功能研究揭示了稳态失活的去极化转变，持续Na+电流增加，快速失活的减缓和其恢复的加速，从而获得功能。在电压钳实验中使用动作电位波形，我们表明在阈下电压下内向Na+电流增加，这可以解释神经元的过度兴奋。我们的研究结果表明，这种突变诱导神经元过度兴奋，导致婴儿癫痫与有利的结果。
Missense mutations in SCN2A, encoding the brain sodium channel NaV1.2, have been described in benign familial neonatal-infantile seizures (BFNIS), a self-limiting disorder, whereas several SCN2A de novo nonsense mutations have been found in patients with more severe phenotypes including epileptic encephalopathy. We report a family with BFNIS originating from Madagascar. Onset extended from 3 to 9 months of age. Interictal EEGs were normal. In two patients, ictal electroencephalography (EEG) studies showed partial seizure patterns with secondary generalization in one. Seizures remitted before 18 months of age, with or without medication. Intellectual development was normal. A novel missense mutation of SCN2A, c.4766A>G/p.Tyr1589Cys, was found in a highly conserved region of NaV1.2 (D4/S2-S3). Functional studies using heterologous expression in tsA201 cells and whole-cell patch clamping revealed a depolarizing shift of steady-state inactivation, increased persistent Na+ current, a slowing of fast inactivation and an acceleration of its recovery, thus a gain-of-function. Using an action potential waveform in a voltage-clamp experiment we indicated an increased inward Na+ current at subthreshold voltages, which can explain a neuronal hyperexcitability. Our results suggest that this mutation induces neuronal hyperexcitability, resulting in infantile epilepsy with favorable outcome.