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

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

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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.

Paroxysmal kinesigenic dyskinesiaKCNA1Loss-of-functionGain-of-functionChannelopathyEpisodic ataxia type 1

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

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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 31

MOE Frontier Science Center for Brain Science and Brain-machine Integration,School of Brain Science and Brain Medicine,Zhejiang University,Hangzhou,Zhejiang 310012,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of China

821015268217123881330025

2024

10.1016/j.jgg.2024.03.013

遗传学报
中国遗传学会 中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD
影响因子：0.821
ISSN：1673-8527
年,卷(期)：2024.51(8)
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