ANK2 H931Y突变与心律失常的机制研究

ANK2 H931Y Variant Confers in vivo Arrhythmia Phenotypes

目的构建ANK2 p.H931Y突变的基因敲入小鼠模型,分析心律失常与ANK2 p.H931Y突变的相关性。方法从一个心律失常家系病例中发现了ANK2 p.H931Y突变,使用生物信息学软件对发现的潜在致病突变进行致病性分析和功能预测,将从全外显子组测序中得到的突变进行Sanger测序进行验证。构建ANK2 p.H931Y基因敲入小鼠,使用动态心电图分析系统监测其心电表型。结果在心律失常家系的2例房室传导阻滞的患者中发现了一种罕见的ANK2 p.H931Y杂合突变。ANK2在体内表现为转录水平表达减少,但蛋白水平的表达没有显著差异。ANK2 p.H931Y小鼠显示心率、房室和心室内传导的改变,以及复极的改变。此外,ANK2 p.H931Y小鼠表现出胺碘酮应激性心律失常。结论ANK2 p.H931Y突变会导致心律失常。

Objective We found ANK2 p.H931Y mutation in an arrhythmia family case and the knockin mice carrying the p.H931Y mutation was constructed to further analyze the correlation between arrhythmia and ANK2 p.H931Y mutation.Methods Using bioinformatics software to perform pathogenicity analysis and function prediction of potential pathogenic mutations found.The ANK2 p.H931Y mutation by whole-exome sequencing were validated by Sanger sequencing.We constructed a new“knockin”animal model harboring ANK2 p.H931Y variant and the electrocardiographic recordings was monitored by using dynamic cardiograph analysis system.Results We detected a rare,heterozygous ANK2 variant(p.H931Y)in 2 related patients with atrioventricular block.This variant was localized to the connection between the Membranebinding domain and Spectrin-binding domain of ANK2.Ank2 displays reduced posttranslational expression in vivo.However,posttranslational expression levels,as well as the localization of ANK2,were indistinguishable between the WT and KI mice.Ank2 p.H931Y mice displays changes in heart rate,atrioventricular and intraventricular conduction,and alterations in repolarization.Furthermore,Ank2 p.H931Y mice displays amiodarone-induced arrhythmias.Conclusion Our findings support in vivo arrhythmogenic phenotypes of ANK2 p.H931Y variant.