PDF(Pubmed)
Abstract：
Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the SCN5A gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel SCN5A mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
摘要：
Brugada综合征（BrS）是一种罕见的遗传性心律失常，可能导致致命的室性心动过速或纤颤，主要发生在没有心脏结构问题的年轻人的休息或睡眠期间。它增加了心源性猝死的风险，其特征是心电图上的ST段抬高异常。虽然BrS有不同的遗传起源，可以对SCN5A基因的突变进行分析，编码Nav1.5钠通道。我们的研究集中在三个新的SCN5A突变上（p。A344S,p.N347K,和p.D349N）在无关的BrS家族中发现。使用膜片钳实验，我们发现这些突变破坏了钠电流：p.A344S降低了电流密度，而p.N347K和p.D349N完全废除了它，当与正常通道共表达时，导致电压依赖性和失活动力学改变。我们还探讨了美西律治疗的效果，可以调节离子通道功能。有趣的是,p.N347K和p.D349N突变对治疗反应良好，拯救电流密度，而p.A344S显示反应有限。结构分析显示这些突变位于通道的关键区域，影响其稳定性和功能。这项研究通过揭示基因突变之间的复杂关系，加深了我们对BrS的理解。离子通道行为，和潜在的治疗干预措施。
