Sodium Channels and Cardiac Arrhythmias

描述(申请人提供)：众所周知，单基因紊乱会引起心脏动作电位的改变，从而导致危及生命的心律失常。虽然这项关于遗传性通道病的工作对我们理解心律失常的机制有很大的贡献，但导致心律失常的单基因紊乱是罕见的。有趣的是，人们还认识到，即使是常见的心律失常形式，如房颤和室颤，也可以是家族性的。然而，这些患者的遗传方式和临床表型是复杂的。事实上，与长QT间期(LQT)或Brugada综合征(BRS)等常染色体显性遗传病类似，这些更常见的心律失常也表现出不同的外显性。有几个流行的假说试图解释为什么特定的基因表达模式可能会产生不同的表型表达，即基因-表型不一致。重要的是，越来越多的证据表明，离子通道多态性等疾病修饰基因可以影响离子通道的功能，导致基因-表型不一致。事实上，PI最近证明，常见的钠通道多态H558R是一种疾病修饰基因，它导致了在许多BRS和LQT3家系中出现的基因型-表型不一致。该多态性能够恢复突变的BRS通道的运输，并恢复突变的LQT3通道的门控动力学，从而使钠通道功能完全正常化。因此，这就解释了为什么携带该基因多态并伴有致病突变的患者明显缺乏临床表型。因此，这一提议的一般假设是钠通道的多态导致了可变外显现象。在这项建议中，PI将通过主要使用从BRS和LQT3大家系获得的信息来阐明这些疾病所涉及的基因-表型不一致。这些与心脏性猝死相关的相对罕见的遗传综合征家族为我们提供了一个独特的机会来确定疾病表型变化的复杂现象。其具体目的是：1.确定钠通道基因多态性在Brugada和长QT_3综合征中的作用。2.探讨SCN5A基因多态性对突变钠通道功能的调控机制。3.发展基因治疗方法，利用基因多态来挽救功能障碍的通道。评估LQTS和BRS易感性的变异性将为分析其他复杂的基因-环境相互作用提供一个框架，这些基因-环境相互作用可能适用于更常见的心源性猝死。此外，了解多态调节突变通道的机制也将提供对离子通道组装和结构的基本理解。重要的是，基因多态可能成为未来旨在拯救功能障碍的离子通道的治疗的目标。 公共卫生相关性：这项工作将为遗传性心律失常的基因-表型变异性提供重要的见解。对于心脏病专家来说，这是至关重要的，他们要选择更有可能从昂贵且高风险的治疗中受益的家庭成员，即植入的除颤器。还将开发一种基因疗法来治疗心律失常。

DESCRIPTION (provided by applicant): It is well-known that monogenic disorders produce alterations of the cardiac action potential that lead to life threatening arrhythmias. Although this work on inheritable channelopathies has greatly contributed to our understanding of arrhythmia mechanisms, monogenic disorders leading to arrhythmias are rare. Interestingly, it is also recognized that even common forms of arrhythmias, such as atrial and ventricular fibrillation can be familial. However, the pattern of inheritance and clinical phenotypes of these patients are complex. In fact, similar to channelopathies such as Long QT (LQT) or Brugada Syndrome (BrS) which are autosomal dominant diseases, these more common arrhythmias also display variable penetrance. There are several prevailing hypotheses that have attempted to explain why a particular gene expression pattern might produce variable phenotypic expression i.e. genotype-phenotype discordance. Importantly, there is emerging evidence indicating that disease modifying genes such as ion channel polymorphisms, can affect the function of ion channels leading to genotype-phenotype discordance. In fact, the PI recently demonstrated that the common sodium channel polymorphism H558R is a disease modifying gene which contributes to the genotype- phenotype discordance seen in multiple families with BrS and LQT3. This polymorphism was able to restore trafficking of mutant BrS channels, and restore the gating kinetics of mutant LQT3 channels resulting in complete normalization of sodium channel function. Thus, this explains the apparent absence of a clinical phenotype in patients carrying the polymorphism along with a disease causing mutation. Therefore, the general hypothesis for this proposal is that sodium channel polymorphisms contribute to the variable penetrance phenomenon. In this proposal, the PI will shed-light on the genotype-phenotype discordance involved in these diseases by primarily using information obtained from large BrS and LQT3 families. These families affected with relatively rare inherited syndromes that relate to sudden cardiac death provide us with a unique opportunity to ascertain the complex phenomenon of variable phenotypic expression of diseases. The specific aims are to: 1. Determine the role of sodium channel polymorphisms in Brugada and Long QT 3 Syndrome. 2. Investigate the mechanisms by which SCN5A polymorphisms can modulate the function of mutated sodium channels. 3. Develop gene therapy approaches, using genetic polymorphisms, to rescue dysfunctional channels. Assessing variability in susceptibility to LQTS and BrS will provide a framework for analysis of other complex gene-environment interactions that may apply to the more common form of sudden cardiac death. Additionally, understanding the mechanisms by which a polymorphism can modulate a mutated channel will also provide fundamental understanding of ion channels assembly and structure. Importantly, gene polymorphisms could become a target for future therapies aimed at rescuing dysfunctional ion channels. PUBLIC HEALTH RELEVANCE: This work will provide important insights for the genotype-phenotype variability seen in inherited arrhythmias. This is crucial for cardiologists to select family members who will more likely benefit from an expensive and risky therapy, the implanted defibrillator. A gene therapy approach will also be developed to treat arrhythmias.