Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3
文献类型：期刊论文
| 作者 | Wu, Xiaorong4,5; Gong, Jili4,5; Qiu, Li3,4; Yang, Guimei3,4; Yuan, Hui3,4; Shen, Xiangchun5; Shen, Yanwen1,2; Tian, Fuyun4; Gao, Zhaobing3,4,5
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| 刊名 | NEUROSCIENCE BULLETIN
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| 出版日期 | 2025-03-17 |
| 页码 | 11 |
| 关键词 | KCNQ3 Self-limited familial neonatal epilepsy Neurodevelopmental disorder Pynegabine Amitriptyline Electrophysiology |
| ISSN号 | 1673-7067 |
| DOI | 10.1007/s12264-025-01378-4 |
| 通讯作者 | Shen, Yanwen(lindia10597@163.com) ; Tian, Fuyun(tianfuyun@zidd.ac.cn) ; Gao, Zhaobing(zbgao@simm.ac.cn) |
| 英文摘要 | The KCNQ potassium channels play a crucial role in modulating neural excitability, and their dysfunction is closely associated with epileptic disorders. While variants in KCNQ2 have been extensively studied, KCNQ3-related disorders have rarely been reported. With advances in next-generation sequencing technologies, an increasing number of cases of KCNQ3-related disorders have been identified. However, the correlation between genotype and phenotype remains poorly understood. In this study, we established a variant library consisting of 24 missense mutations in KCNQ3 and introduced these mutations into three different template types: KCNQ3, KCNQ3-A315T (Q3*), and KCNQ3-KCNQ2 tandem (Q3-Q2). We then analyzed the effects of these mutations on the KCNQ3 channel function using patch-clamp recording. The most informative parameter across all three backgrounds was the current density of the mutant channels. The current density patterns in the Q3* and Q3-Q2 backgrounds were similar, with most mutations resulting in an almost complete loss of function (LOF), they were concentrated in the pore-forming domain of KCNQ3. In contrast, mutations in the voltage-sensing domain or C-terminus did not show significant differences from the wild-type channel. Interestingly, these LOF mutations were typically associated with self-limited familial neonatal epilepsy, while neurodevelopmental disorders (NDD) were more closely associated with mutations that did not significantly differ from the wild-type. V1/2, another important parameter of the electrophysiological properties, could not be accurately determined in the majority of KCNQ3 mutations due to its nearly complete LOF in the Q3* and Q3-Q2 backgrounds. Intriguingly, the V1/2 of functional mutations were primarily leftward shifted, indicating a gain-of-function (GOF) effect, which was typically associated with NDD. In addition to previously reported mutations, we identified G553R as a novel GOF mutation. In the co-transfection background, parameters such as V1/2 could be determined, but the dysfunctional effects of these mutations were mitigated by the co-expression of wild-type KCNQ3 and KCNQ2 subunits, resulting in no significant differences between most mutations and the wild-type channel. Furthermore, we applied KCNQ modulators to reverse the electrophysiological abnormalities caused by KCNQ3 variants. The LOF mutations were reversed by the application of Pynegabine (HN37), a KCNQ opener, while the GOF mutation responded well to Amitriptyline (AMI), a KCNQ inhibitor. These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making. |
| WOS关键词 | POTASSIUM CHANNEL ; VOLTAGE SENSOR ; MUTATIONS ; EPILEPSY ; PATHOPHYSIOLOGY ; ENCEPHALOPATHY ; CONVULSIONS ; CALMODULIN ; SEIZURES ; K(V)7.2 |
| 资助项目 | High-level New RD Institute[2019B090904008] ; High-level Innovative Research Institute[2021B0909050003] ; Department of Science and Technology of Guangdong Province ; Guangdong Basic and Applied Basic Research Foundation[E404005] ; Zhongshan Municipal Bureau of Science and Technology[221018194369472] ; Zhongshan Municipal Bureau of Science and Technology[CXTD2202013] |
| WOS研究方向 | Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:001446107600001 |
| 出版者 | SPRINGER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316677]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shen, Yanwen; Tian, Fuyun; Gao, Zhaobing |
| 作者单位 | 1.Peoples Liberat Army Gen Hosp, Chinese PLA Gen Hosp, Fac Pediat, Grad Sch, Beijing 100853, Peoples R China 2.Chinese Acad Sci, Brain Cognit & Brain Dis Inst, Shenzhen Inst Adv Technol, Translat Res Ctr Nervous Syst, Shenzhen 518055, Guangdong, Peoples R China 3.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China 4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 5.Guizhou Med Univ, Sch Pharmaceut Sci, Guiyang 550025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Xiaorong,Gong, Jili,Qiu, Li,et al. Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3[J]. NEUROSCIENCE BULLETIN,2025:11. |
| APA | Wu, Xiaorong.,Gong, Jili.,Qiu, Li.,Yang, Guimei.,Yuan, Hui.,...&Gao, Zhaobing.(2025).Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3.NEUROSCIENCE BULLETIN,11. |
| MLA | Wu, Xiaorong,et al."Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3".NEUROSCIENCE BULLETIN (2025):11. |
入库方式： OAI收割
来源：上海药物研究所
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