Heterozygous KCNJ10 Variants Affecting Kir4.1 Channel Cause Paroxysmal Kinesigenic Dyskinesia

作者：Xiaojun Huang, Xin Fu, Jingying Wu, Xin Cheng, Xiaoqi Hong, Ziyi Li, Lan Zheng, Qing Liu, Shendi Chen, Beisha Tang, Yuwu Zhao, Xiao‐Rong Liu, Xunhua Li, Xiaoli Liu, Zaiwei Zhou, Li Wu, Kan Fang, Ping Zhong, Mei Zhang, Xinghua Luan, Wotu Tian, Xiaoping Tong, Li Cao · 发表于：Movement Disorders · 年份：2024 · DOI：10.1002/mds.30025 · 被引用次数：8 · 研究领域：Epilepsy research and treatment、Genetic Neurodegenerative Diseases、Ion channel regulation and function

BACKGROUND: More than 60% of paroxysmal kinesigenic dyskinesia (PKD) cases are of uncertain variants. OBJECTIVE: The aim was to elucidate novel genetic contribution to PKD. METHODS: A total of 476 probands with uncertain genetic causes were enrolled for whole-exome sequencing. A method of case-control analysis was applied to identify the candidate genes. Whole-cell patch-clamp recording was applied to verify the electrophysiological impact of the identified variants. A mouse model with cerebellar heterozygous knockout of the candidate gene was developed via adeno-associated virus injection, and dystonia-like phenotype inducement and rotarod tests were performed. In vivo multiunit electrical recording was applied to investigate the change in neural excitability in knockout mice. RESULTS: Heterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) clustered in PKD patients were compared with those in the control groups. Fifteen variants were detected in 16 of 522 probands (frequency = 3.07%). Patients with KCNJ10 variants tended to have a milder manifestation compared to those with PRRT2 (proline-rich transmembrane protein 2) variants. KCNJ10 variants partially altered the transmembrane location of inwardly rectifying potassium channel 4.1 (Kir4.1). The Kcnj10 expression is consistent with the natural course of PKD. Variants resulted in different degrees of reduction in cell Kir4.1 currents, and mice with heterozygous conditional knockout of Kc...