Sodium Channels and Cardiac Arrhythmias

钠通道和心律失常

• 批准号: 8041027
• 负责人: Isabelle Deschenes
• 金额: $ 39.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041027
• 关键词: Action Potentials; Affect; Age; Arrhythmia; Atrial Fibrillation; Cardiac; Cell membrane; Complex; Defibrillators; Disease; Dominant-Negative Mutation; Family; Family member; Future; Gene Expression; Gene-Modified; Genes; Genetic Polymorphism; Genotype; Heart Atrium; Hormones; Implant; In Vitro; Individual; Inheritance Patterns; Inherited; Ion Channel; Kinetics; Lead; Life; Light; Measures; Modification; Mutate; Mutation; Patients; Pattern; Penetrance; Peptides; Phenotype; Post-Translational Protein Processing; Predisposition; Proteins; Rare Diseases; Role; Sodium Channel; Solid; Stress; Structure; Syndrome; Techniques; Testing; Ventricular Fibrillation; Work; clinical phenotype; disease-causing mutation; functional restoration; gene environment interaction; gene therapy; insight; mutant; novel; public health relevance; sudden cardiac death; therapy design; trafficking

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.

描述（由申请方提供）：众所周知，单基因疾病会导致心脏动作电位改变，从而导致危及生命的心律失常。虽然这项工作对遗传性通道病的心律失常机制的理解作出了很大的贡献，单基因疾病导致心律失常是罕见的。有趣的是，人们还认识到，即使是常见形式的心律失常，如心房和心室颤动，也可能是家族性的。然而，这些患者的遗传模式和临床表型是复杂的。事实上，与常染色体显性遗传疾病如长QT（LQT）或Brugada综合征（BrS）等通道病相似，这些更常见的心律失常也显示出可变的心律失常。有几种流行的假说试图解释为什么一个特定的基因表达模式可能会产生可变的表型表达，即基因型-表型不一致。重要的是，有新的证据表明，疾病修饰基因，如离子通道多态性，可以影响离子通道的功能，导致基因型-表型不一致。事实上，PI最近证明，常见钠通道多态性H558 R是一种疾病修饰基因，其导致在多个BrS和LQT 3家族中观察到的基因型-表型不一致性。这种多态性能够恢复突变型BrS通道的运输，并恢复突变型LQT 3通道的门控动力学，导致钠通道功能完全正常化。因此，这解释了携带该多态性沿着致病突变的患者中临床表型的明显缺失。因此，这一提议的一般假设是钠通道多态性有助于可变的跨膜转运现象。在这个提议中，PI将主要使用从大BrS和LQT 3家族获得的信息来阐明这些疾病中涉及的基因型-表型不一致性。这些家庭受到相对罕见的遗传综合征，涉及心脏性猝死为我们提供了一个独特的机会，以确定复杂的现象，疾病的可变表型表达。具体目标是：1.确定钠通道多态性在Brugada和长QT 3综合征中的作用。2.研究SCN 5A多态性调节突变钠通道功能的机制。3.开发基因治疗方法，利用遗传多态性，以挽救功能失调的渠道。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，这些相互作用可能适用于更常见的心脏性猝死形式。此外，了解多态性可以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，基因多态性可能成为未来治疗的目标，旨在挽救功能失调的离子通道。 公共卫生相关性：这项工作将为遗传性心律失常的基因型-表型变异性提供重要的见解。这对于心脏病专家选择更有可能从昂贵和危险的治疗中受益的家庭成员至关重要，植入除颤器。还将开发一种基因治疗方法来治疗心律失常。