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

摘要KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channel α subunit.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.

作者 Wan-Bing Sun ^[1] Jing-Xin Fu ^[2] Yu-Lan Chen ^[2] Hong-Fu Li ^[1] Zhi-Ying Wu ^[3] Dian-Fu Chen ^[4] 学术成果认领

作者单位 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;Nanhu Brain-computer Interface Institute,Hangzhou,Zhejiang 314050,China ^[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] 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;Nanhu Brain-computer Interface Institute,Hangzhou,Zhejiang 314050,China;MOE Frontier Science Center for Brain Science and Brain-machine Integration,School of Brain Science and Brain Medicine,Zhejiang University,Hangzhou,Zhejiang 310012,China ^[3] 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;MOE Frontier Science Center for Brain Science and Brain-machine Integration,School of Brain Science and Brain Medicine,Zhejiang University,Hangzhou,Zhejiang 310012,China ^[4]

关键词 Paroxysmal kinesigenic dyskinesia KCNA1 Loss-of-function Gain-of-function Channelopathy Episodic ataxia type 1

栏目名称

Original Research

DOI 10.1016/j.jgg.2024.03.013

发布时间 2024-09-03（万方平台首次上网日期，不代表论文的发表时间）

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