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A Novel KCNQ2 Gain-of-Function Variant I134N Causes Severe Developmental and Epileptic Encephalopathy

文献类型：期刊论文

作者Zeng, Fengmei4,6; Ye, Xiaoying3,4; Gao, Zhaobing3,4,6; Tian, Fuyun3; Shen, Yanwen1,2,5
刊名AMERICAN JOURNAL OF MEDICAL GENETICS PART A
出版日期2026-01-06
页码8
关键词amitriptyline developmental and epileptic encephalopathy electrophysiology gain-of-function KCNQ2 channel
ISSN号1552-4825
DOI10.1002/ajmga.70044
通讯作者Gao, Zhaobing(zbgao@simm.ac.cn) ; Tian, Fuyun(tianfuyun@zidd.ac.cn) ; Shen, Yanwen(yw.shen@siat.ac.cn)
英文摘要Missense variants in the KCNQ2 gene can cause developmental and epileptic encephalopathy (DEE). While most KCNQ2-DEE cases are attributed to loss-of-function (LOF) mutations, gain-of-function (GOF) mutations have also been implicated in the disorder. This study describes the clinical features of a DEE patient with a KCNQ2 mutation in the voltage-sensing domain (VSD) and analyzes the variant's electrophysiological properties. Whole-exome sequencing was performed to identify the genetic variant. Whole-cell patch-clamp electrophysiology was used to characterize the functional effects of the mutant channel, both alone and in combination with KCNQ3 subunits at a 1:1:2 ratio to mimic the patient's allele dosage. The effect of amitriptyline (AMI) on channel activity was also evaluated. A three-year-old female with early-onset epileptic encephalopathy presented with intractable seizures, developmental regression, microcephaly, transient thyroid dysfunction, and a mixed EEG pattern of hypsarrhythmia and intermittent burst-suppression. A de novo KCNQ2 variant (c.401T>A, p.Ile134Asn) located in the conserved S2 transmembrane domain was identified and classified as likely pathogenic. Electrophysiological analysis showed that the KCNQ2-I134N mutation caused a hyperpolarizing shift in voltage-dependent activation and significantly increased current density, indicating a GOF effect. This GOF phenotype persisted when the mutant subunit was co-expressed with KCNQ3 and under a transfection ratio mimicking the patient's genotype. The hyperactivity of the mutant channel was effectively suppressed by amitriptyline. We report a novel GOF variant (I134N) in the KCNQ2 gene associated with DEE. The KCNQ blocker amitriptyline effectively suppressed mutant channel hyperactivity, suggesting its potential as a targeted therapeutic option for patients with this pathogenic variant.
WOS关键词PATHOPHYSIOLOGY ; MUTATIONS
资助项目Basic and Applied Basic Research Foundation of Guangdong Province[E404005] ; the Department of Science and Technology of Guangdong Province[2019B090904008] ; the Department of Science and Technology of Guangdong Province[2021B0909050003] ; Zhongshan Science and Technology Bureau[CXTD2022013] ; Zhongshan Municipal Natural Science Foundation[221018194369472]
WOS研究方向Genetics & Heredity
语种英语
WOS记录号WOS:001654533800001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/322548]  
专题中国科学院上海药物研究所
通讯作者Gao, Zhaobing; Tian, Fuyun; Shen, Yanwen
作者单位1.Shenzhen Univ Adv Technol, Fac Life & Hlth Sci, Shenzhen, Guangdong, Peoples R China
2.Chinese Acad Sci, Shenzhen Inst Adv Technol, Translat Res Ctr Nervous Syst Brain Cognit & Brain, Shenzhen, Guangdong, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
5.Chinese Peoples Liberat Army Gen Hosp, Med Sch Chinese Peoples Liberat Army, Dept Pediat, Beijing, Peoples R China
6.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Zeng, Fengmei,Ye, Xiaoying,Gao, Zhaobing,et al. A Novel KCNQ2 Gain-of-Function Variant I134N Causes Severe Developmental and Epileptic Encephalopathy[J]. AMERICAN JOURNAL OF MEDICAL GENETICS PART A,2026:8.
APA Zeng, Fengmei,Ye, Xiaoying,Gao, Zhaobing,Tian, Fuyun,&Shen, Yanwen.(2026).A Novel KCNQ2 Gain-of-Function Variant I134N Causes Severe Developmental and Epileptic Encephalopathy.AMERICAN JOURNAL OF MEDICAL GENETICS PART A,8.
MLA Zeng, Fengmei,et al."A Novel KCNQ2 Gain-of-Function Variant I134N Causes Severe Developmental and Epileptic Encephalopathy".AMERICAN JOURNAL OF MEDICAL GENETICS PART A (2026):8.

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来源：上海药物研究所

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