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SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine 期刊论文

编号：

2892740f-5ad4-4a43-969b-13e93fb1bad5
作者：

Zhang, Shuzhang#^[1]Zhang, Zhiping^[1];Shen, Yuan^[2,3]Zhu, Yudan^[2,3]Du, Kun^[4];Guo, Jingkang^[1];Ji, Yonghua*^[1,5]Tao, Jie*^[2,3,6]
语种：

英文
期刊：

NEUROSCIENCE BULLETIN ISSN：1673-7067 2020 年 36 卷 1 期 (11 - 24) ; JAN
收录：
关键词：

Voltage-gated sodium channel SCN9A Epilepsy Electrophysiological function Oxcarbazepine Sensitivity
摘要：

Genetic mutants of voltage-gated sodium channels (VGSCs) are considered to be responsible for the increasing number of epilepsy syndromes. Previous research has indicated that mutations of one of the VGSC genes, SCN9A (Nav1.7), result in febrile seizures and Dravet syndrome in humans. Despite these recent efforts, the electrophysiological basis of SCN9A mutations remains unclear. Here, we performed a genetic screen of patients with febrile seizures and identified a novel missense mutation of SCN9A (W1150R). Electrophysiological characterization of different SCN9A mutants in HEK293T cells, the previously-reported N641Y and K655R variants, as well as the newly-found W1150R variant, revealed that the current density of the W1150R and N641Y variants was significantly larger than that of the wild-type (WT) channel. The time constants of recovery from fast inactivation of the N641Y and K655R variants were markedly lower than in the WT channel. The W1150R variant caused a negative shift of the G-V curve in the voltage dependence of steady-state activation. All mutants displayed persistent currents larger than the WT channel. In addition, we found that oxcarbazepine (OXC), one of the antiepileptic drugs targeting VGSCs, caused a significant shift to more negative potential for the activation and inactivation in WT and mutant channels. OXC-induced inhibition of currents was weaker in the W1150R variant than in the WT. Furthermore, with administering OXC the time constant of the N641Y variant was longer than those of the other two SCN9A mutants. In all, our results indicated that the point mutation W1150R resulted in a novel gain-of-function variant. These findings indicated that SCN9A mutants contribute to an increase in seizure, and show distinct sensitivity to OXC.
推荐引用方式
GB/T 7714：

Zhang Shuzhang,Zhang Zhiping,Shen Yuan, et al. SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine [J].NEUROSCIENCE BULLETIN,2020,36(1):11-24.
APA：

Zhang Shuzhang,Zhang Zhiping,Shen Yuan,Zhu Yudan,&Tao Jie.(2020).SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine .NEUROSCIENCE BULLETIN,36(1):11-24.
MLA：

Zhang Shuzhang, et al. "SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine" .NEUROSCIENCE BULLETIN 36,1(2020):11-24.
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