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SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs

文献类型：期刊论文

作者Guo, Qian-bei2,3; Zhan, Li3; Xu, Hai-yan3; Gao, Zhao-bing1,2,3; Zheng, Yue-ming3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2022-07-27
页码10
关键词early infantile epileptic encephalopathy type 13 SCN8A gain-of-function mutation antiepileptic drugs phenytoin carbamazepine
ISSN号1671-4083
DOI10.1038/s41401-022-00955-x
通讯作者Gao, Zhao-bing(zbgao@simm.ac.cn) ; Zheng, Yue-ming(zhengyueming@simm.ac.cn)
英文摘要De novo missense mutations in SCN8A gene encoding voltage-gated sodium channel Na(V)1.6 are linked to a severe form of early infantile epileptic encephalopathy named early infantile epileptic encephalopathy type13 (EIEE13). The majority of the patients with EIEE13 does not respond favorably to the antiepileptic drugs (AEDs) in clinic and has a significantly increased risk of death. Although more than 60 EIEE13-associated mutations have been discovered, only few mutations have been functionally analyzed. In this study we investigated the functional influences of mutations N1466T and N1466K, two EIEE13-associated mutations located in the inactivation gate, on sodium channel properties. Sodium currents were recorded from CHO cells expressing the mutant and wide-type (WT) channels using the whole-cell patch-clamp technique. We found that, in comparison with WT channels, both the mutant channels exhibited increased window currents, persistent currents (I-NaP) and ramp currents, suggesting that N1466T and N1466K were gain-of-function (GoF) mutations. Sodium channel inhibition is one common mechanism of currently available AEDs, in which topiramate (TPM) was effective in controlling seizures of patients carrying either of the two mutations. We found that TPM (100 mu M) preferentially inhibited I-NaP and ramp currents but did not affect transient currents (I-NaT) mediated by N1466T or N1466K. Among the other 6 sodium channel-inhibiting AEDs tested, phenytoin and carbamazepine displayed greater efficacy than TPM in suppressing both I-NaP and ramp currents. Functional characterization of mutants N1466T and N1466K is beneficial for understanding the pathogenesis of EIEE13. The divergent effects of sodium channel-inhibiting AEDs on I-NaP and ramp currents provide insight into the development of therapeutic strategies for the N1466T and N1466K-associated EIEE13.
WOS关键词ACTION-POTENTIAL INITIATION ; PERSISTENT SODIUM CURRENT ; MUSCLE NA+ CHANNELS ; SCN8A-RELATED EPILEPSY ; NA(V)1.6 ; RESIDUES ; INACTIVATION ; NEURONS ; PACEMAKING ; MECHANISM
资助项目National Science Fund for Distinguished Young Scholars[81825021] ; National Natural Science Foundation of China[81773707] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020284] ; Fund of Science and Technology Commission of Shanghai Municipality[19431906000]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000832483400001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/302001]  
专题中国科学院上海药物研究所
通讯作者Gao, Zhao-bing; Zheng, Yue-ming
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Qian-bei,Zhan, Li,Xu, Hai-yan,et al. SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs[J]. ACTA PHARMACOLOGICA SINICA,2022:10.
APA Guo, Qian-bei,Zhan, Li,Xu, Hai-yan,Gao, Zhao-bing,&Zheng, Yue-ming.(2022).SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs.ACTA PHARMACOLOGICA SINICA,10.
MLA Guo, Qian-bei,et al."SCN8A epileptic encephalopathy mutations display a gain-of-function phenotype and divergent sensitivity to antiepileptic drugs".ACTA PHARMACOLOGICA SINICA (2022):10.

入库方式： OAI收割

来源：上海药物研究所

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