SCN9A Epileptic Encephalopathy Mutations Display a Gain-offunction Phenotype and Distinct Sensitivity to Oxcarbazepine

作     者：Shuzhang Zhang Zhiping Zhang Yuan Shen Yudan Zhu Kun Du Jingkang Guo Yonghua Ji Jie Tao Shuzhang Zhang;Zhiping Zhang;Yuan Shen;Yudan Zhu;Kun Du;Jingkang Guo;Yonghua Ji;Jie Tao

作者机构：Institute of Biomembrane and BiopharmaceuticsShanghai UniversityShanghai 200444China Central Laboratory and Department of NeurologyPutuo HospitalShanghai University of Traditional Chinese MedicineShanghai 200062China Department of Clinical LaboratoryXin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 202150China Xinhua Translational Institute for Cancer PainXinhua Hospital Chongming BranchShanghai 202150China Putuo Clinical Medical SchoolAnhui Medical UniversityShanghai 200062China 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2020年第36卷第1期

页      面：11-24页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：We are grateful to Prof.Ren Lai and Shilong Yang(Kunming Institute of Zoology,Chinese Academy of Sciences)for providing the pEZ-Lv206-hNav 1.7 plasmid.This work was supported by the National Natural Science Foundation of China(81603410,31571032,and 31771191) the Shanghai Municipal Commission of Health and Family Planning Foundation(20184Y0086) Innovation Program of Shanghai Municipal Education Commission(15ZZ063) the Research Project of Putuo Hospital,Shanghai University of Traditional Chinese Medicine(2016102A and 2016208A) a Project for Capacity Promotion of Putuo District Clinical Special Disease 

主　　题：Voltage-gated sodium channel SCN9A Epilepsy Electrophysiological function Oxcarbazepine Sensitivity Introduction 

摘      要：Genetic mutants of voltage-gated sodium channels(VGSCs)are considered to be responsible for the increasing number of epilepsy *** research has indicated that mutations of one of the VGSC genes,SCN9A(Navl.7),result in febrile seizures and Dravet syndrome in *** these recent efforts,the electrophysiological basis of SCN9A mutations remains ***,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)*** time constants of recovery from fast inactivation of the N641Y and K655R variants were markedly lower than in the WT *** W1150R variant caused a negative shift of the G-V curve in the voltage dependence of steady-state *** mutants displayed persistent currents larger than the WT *** 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 ***-induced inhibition of currents was weaker in the W1150R variant than in the ***,with administering OXC the time constant of the N641Y variant was longer than those of the other two SCN9A *** all,our results indicated that the point mutation W1150R resulted in a novel gain-of-function *** findings indicated that SCN9A mutants contribute to an increase in seizure,and show distinct sensitivity to OXC.