Both gain-and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia  

作　　者：Wan-Bing Sun Jing-Xin Fu Yu-Lan Chen Hong-Fu Li Zhi-Ying Wu Dian-Fu Chen 

机构地区：[1]Department of Medical Genetics and Center for Rare Diseases,and Department of Neurology,and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation in Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang 310009,China [2]Nanhu Brain-computer Interface Institute,Hangzhou,Zhejiang 314050,China [3]MOE Frontier Science Center for Brain Science and Brain-machine Integration,School of Brain Science and Brain Medicine,Zhejiang University,Hangzhou,Zhejiang 310012,China

出　　处：《Journal of Genetics and Genomics》2024年第8期801-810,共10页遗传学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82101526,82171238,and 81330025)。

摘　　要：KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases.Using the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families.The proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as PKD.The pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected.By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to epilepsy.Thus,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.

关 键 词：Paroxysmal kinesigenic dyskinesia KCNA1 LOSS-OF-FUNCTION GAIN-OF-FUNCTION CHANNELOPATHY Episodicataxiatype1 

分 类 号：R774.1[医药卫生—眼科]