KCNA1基因中的显性负性突变p.Arg324Thr损害发作性共济失调中的Kv1.1通道功能。
Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia.
作者信息
Tristán-Clavijo Enriqueta, Scholl Francisco G, Macaya Alfons, Iglesias Gemma, Rojas Ana M, Lucas Miguel, Castellano Antonio, Martinez-Mir Amalia
机构信息
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Sevilla, Spain.
出版信息
Mov Disord. 2016 Nov;31(11):1743-1748. doi: 10.1002/mds.26737. Epub 2016 Aug 1.
BACKGROUND
Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the α subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients.
METHODS
A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function.
RESULTS
Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation.
CONCLUSIONS
Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. © 2016 International Parkinson and Movement Disorder Society.
背景
发作性共济失调1型是一种罕见的常染色体显性神经疾病，由编码电压门控钾通道Kv1.1的α亚基的KCNA1基因突变引起。已鉴定的突变对通道功能的功能后果与患者的临床表型并不完全相关。
方法
对一个有5名发作性共济失调1型患者的家系进行了临床和遗传学研究，其中1名患者并发癫痫。进行了蛋白质表达、建模和电生理分析以研究Kv1.1功能。
结果
全基因组连锁和候选基因分析揭示了KCNA1基因中的新型杂合突变p.Arg324Thr。编码的突变Kv1.1通道显示电流减少以及激活和失活改变。
结论
综上所述，我们提供了遗传和功能证据，证明KCNA1基因中的突变p.Arg324Thr具有致病性，并通过显性负效应导致发作性共济失调1型。© 2016国际帕金森和运动障碍协会。
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