Epilepsy phenotype and response to KCNQ openers in mice harboring the Kcnq2 R207W voltage-sensor mutation
文献类型：期刊论文
| 作者 | Tian, Fuyun5,6,7; Cao, Birong5,6,7; Xu, Haiyan6; Zhan, Li6; Nan, Fajun6 ; Li, Ning2,3; Taglialatela, Maurizio4; Gao, Zhaobing1,5,6,7
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| 刊名 | NEUROBIOLOGY OF DISEASE
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| 出版日期 | 2022-11-01 |
| 卷号 | 174页码:10 |
| 关键词 | KCNQ2 Epilepsy Mouse model HN37 (pynegabine) |
| ISSN号 | 0969-9961 |
| DOI | 10.1016/j.nbd.2022.105860 |
| 通讯作者 | Taglialatela, Maurizio(mtaglial@unina.it) ; Gao, Zhaobing(zbgao@simm.ac.cn) |
| 英文摘要 | KCNQ2-encoded Kv7.2 subunits play a critical role in balancing neuronal excitability. Mutations in KCNQ2 are responsible for highly-heterogenous epileptic and neurodevelopmental phenotypes ranging from self-limited familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). Pathogenic KCNQ2 variants cluster at the voltage sensor domain (VSD), the pore domain, and the C-terminal tail. Although several knock-in mice harboring Kcnq2 pore variants have been developed, no mouse line carrying Kcnq2 voltage-sensor mutations has been described. KCNQ2-R207W is an epilepsy-causing mutation located in the VSD, mainly affecting voltage-dependent channel gating. To study the physiological consequence of Kcnq2 VSD dysfunction, we generated a Kcnq2-R207W mouse line and analyzed the pathological and pharmacological phenotypes of mutant mice. As a result, both homozygous (Kcnq2RW/RW) and heterozygous (Kcnq2RW/+) mice were viable. While Kcnq2RW/RW mice displayed a short lifespan, growth retardation, and spontaneous seizures, Kcnq2RW/+ mice survived and developed normally, although only a fraction (9/64; 14%) of them showed behavioral-and ECoG-confirmed spontaneous seizures. Kcnq2RW/+ mice displayed increased susceptibility to evoked seizures, which was dramatically ameliorated by treatment with the novel KCNQ opener pynegabine (HN37). Our results show that the Kcnq2-R207W mouse line, the first harboring a Kcnq2 voltage-sensor muta-tion, exhibits a unique epileptic phenotype with both spontaneous seizures and increased susceptibility to evoked seizures. In Kcnq2-R207W mice, the potent KCNQ opener HN37, currently in clinical phase I, shows strong anticonvulsant activity, suggesting it may represent a valuable option for the severe phenotypes of KCNQ2-related epilepsy. |
| WOS关键词 | FAMILIAL NEONATAL CONVULSIONS ; POTASSIUM CHANNELS ; MOUSE MODELS ; GENE ; SEIZURES ; ENCEPHALOPATHY ; INTERNEURONS ; SUPPRESSION ; SPECTRUM ; CURRENTS |
| 资助项目 | High-level new RD institute[2021B0909050003] ; High-level Innovative Research Institute of the Department of Science and Technology of Guangdong Province[81825021] ; National Science Fund for Distinguished Young Scholars[210724194041939] ; Public Welfare and Basic Research Project of Zhongshan City[2017ALCR7C] ; Italian Ministry for University and Research (MIUR)[RF-2019-12370491] ; Italian Ministry of Health[UNI-COM-875299] ; European Commission ; European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ) ; [2019B090904008] |
| WOS研究方向 | Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000867487500010 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/303253]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Taglialatela, Maurizio; Gao, Zhaobing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.HKUST Shenzhen Res Inst, Shenzhen 518057, Peoples R China 3.Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Peoples R China 4.Univ Naples Feder II, Dept Neurosci, I-80131 Naples, Italy 5.Univ Chinese Acad Sci, Beijing, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai, Peoples R China 7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Guangdong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tian, Fuyun,Cao, Birong,Xu, Haiyan,et al. Epilepsy phenotype and response to KCNQ openers in mice harboring the Kcnq2 R207W voltage-sensor mutation[J]. NEUROBIOLOGY OF DISEASE,2022,174:10. |
| APA | Tian, Fuyun.,Cao, Birong.,Xu, Haiyan.,Zhan, Li.,Nan, Fajun.,...&Gao, Zhaobing.(2022).Epilepsy phenotype and response to KCNQ openers in mice harboring the Kcnq2 R207W voltage-sensor mutation.NEUROBIOLOGY OF DISEASE,174,10. |
| MLA | Tian, Fuyun,et al."Epilepsy phenotype and response to KCNQ openers in mice harboring the Kcnq2 R207W voltage-sensor mutation".NEUROBIOLOGY OF DISEASE 174(2022):10. |
入库方式： OAI收割
来源：上海药物研究所
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