Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3.
10.1007/s12264-025-01378-4
- Author:
Xiaorong WU
1
;
Jili GONG
1
;
Li QIU
2
;
Guimei YANG
2
;
Hui YUAN
2
;
Xiangchun SHEN
1
;
Yanwen SHEN
3
,
4
;
Fuyun TIAN
5
;
Zhaobing GAO
6
Author Information
1. School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China.
2. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
3. Translational Research Center for the Nervous System, Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China. lindia10597@
4. com.
5. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. tianfuyun@zidd.ac.cn.
6. School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China. zbgao@simm.ac.cn.
- Publication Type:Journal Article
- Keywords:
Amitriptyline;
Electrophysiology;
KCNQ3;
Neurodevelopmental disorder;
Pynegabine;
Self-limited familial neonatal epilepsy
- MeSH:
KCNQ3 Potassium Channel/genetics*;
Humans;
Mutation, Missense/genetics*;
KCNQ2 Potassium Channel/genetics*;
Patch-Clamp Techniques;
HEK293 Cells;
Animals;
Phenylenediamines/pharmacology*;
Carbamates
- From:
Neuroscience Bulletin
2025;41(9):1511-1521
- CountryChina
- Language:English
-
Abstract:
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.
