Abstract：
Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.
摘要：
Brugada综合征（BrS）是一种遗传性疾病，其特征是心电图（ECG）上右心前导联的右心前ST段抬高，以及危及生命的室性心律失常和心源性猝死（SCD）的高风险。在BrS患者中，负责基因的突变尚未得到充分表征，除了SCN5A基因.我们发现了一种新的遗传变异,c.1189C>T（p。R397C),在KCNH2基因中，无症状男性先证者诊断为BrS和轻度QTc缩短。我们假设此变体可能会改变IKr电流，并且可能是罕见的非SCN5A相关形式的BrS的原因。为了评估其致病性，我们对中国仓鼠卵巢细胞中KCNH2突变重建的IKr进行了膜片钳分析,并将其表型与野生型进行了比较.似乎R397C突变不影响IKr密度，但有助于激活，阻碍了hERG通道的失活，并增加窗口电流的幅度，表明p.R397C是功能增益突变。计算机模拟表明，这种错义突变可能导致心脏动作电位的缩短。
