Positional Cloning and Candidate Gene Approach to Familial Atrial Fibrilation

描述(申请人提供)：房颤(房颤)是临床上最常见的心律失常，在美国老龄化人口中达到流行的程度。大多数房颤是继发性的，但高达30%的患者没有明显的原因，据说是“孤立性”或特发性房颤。我们和其他人已经证明了孤立性房颤有大量的可遗传成分，并且已经证明孤立性房颤是一种表型和遗传上的异质性疾病。因此，人们越来越认识到房颤可能有家族易感性，事实上，已经描述了一些遗传位点。此外，据报道，在孤立病例和小型家系中，编码心肌钾通道和缝隙连接的基因发生了突变。虽然存在遗传形式的房颤，但表型复杂性对确定突变携带者并从而识别致病基因的努力有限。在一个较大的房颤家系中，我们在第5号染色体上定位了一个新的房颤基因座，使用延长的信号平均P波持续时间作为房颤的中间或内表型。在具体目标1中，我们建议在一大批家族性、散发性和典型的房颤患者中，确定5p15基因座上与孤立性房颤有关的基因，并评估其对房颤的作用。人类心脏钠通道负责心脏动作电位的快速去极化上升，是抗心律失常药物的分子靶点，其中一些药物在治疗房性心律失常方面有效。越来越多的证据支持编码人类心脏钠通道的基因SCN5A在房颤中的作用。SCN5A基因突变与遗传性室性心律失常(先天性长QT间期综合征和Brugada综合征)、心脏传导受损或这些表型的组合有关。其中一些综合征包括房颤，最近还发现SCN5A突变与家族性扩张型心肌病和房性心律失常有关。因此，我们对375例房颤患者包括118例孤立性房颤患者的SCN5A基因进行了重新测序，发现了19个罕见的错义突变，其中包括22个先证者的8个新等位基因(5.9%)。我们推测其中一些基因变异与房颤易感性有关。在特定的目标2中，我们将通过确定每个变异携带者的扩展家系并将基因型与房颤的存在相关联来检验这一假设。临床遗传学研究将得到特定目标3的实验的补充，这些实验将确定在房颤先证者中发现的SCN5A变异的电生理后果。这些研究将使用异源表达的重组人SCN5A钠通道和膜片钳记录技术。突变和变异的功能特征不仅可以验证它们与疾病的相关性，还可以深入了解房颤的病理生理机制。对导致房颤的不同机制的更好的理解是开发针对这种常见和病态疾病的亚型特异性治疗的第一步。公共卫生相关性：房颤(房颤)是临床实践中最常见的心律失常。在这项研究中，我们试图确定可能使个人患上这种心律失常的基因。更好地了解房颤的病因将为我们提供治疗这种常见和病态疾病的新方法。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice, reaching epidemic proportions in the aging U.S. population. Most AF is secondary to other conditions but up to 30% of patients have no obvious cause and are said to have "lone" or idiopathic AF. We and others have demonstrated that lone AF has a substantial heritable component and have shown that lone AF is phenotypically and genetically a heterogeneous disorder. It is therefore increasingly appreciated that there may be a familial predisposition to AF, and indeed a number of genetic loci have been described. In addition, mutations in genes encoding cardiac potassium channels and gap junctions have been reported in isolated cases and small kindreds. While inherited forms of AF exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. In a large AF kindred, we have mapped a novel locus for AF on chromosome 5 using a prolonged signal-averaged P-wave duration as an intermediate or endophenotype for AF. In Specific Aim 1, we propose to identify the gene responsible for lone AF at the 5p15 locus and assess its contribution to AF in a large cohort of patients with familial, sporadic and typical AF. The human cardiac sodium channel is responsible for the fast depolarization upstroke of the cardiac action potential and is a molecular target for antiarrhythmic drugs some of which are effective in treating atrial arrhythmias. There is mounting evidence supporting the role of SCN5A, the gene encoding the human cardiac sodium channel, in AF. Mutations in SCN5A have been associated with inherited susceptibility to ventricular arrhythmias (congenital long QT syndrome and Brugada syndrome), impaired cardiac conduction or a combination of these phenotypes. Some of these syndromes include AF, and SCN5A mutations have also recently been associated with familial dilated cardiomyopathy and atrial arrhythmias. Therefore, we resequenced the gene in 375 AF patients including 118 with lone AF for variants in SCN5A and identified 19 rare missense variants including 8 novel alleles in 22 probands (5.9%). We hypothesize that some of these gene variants are responsible for AF susceptibility. In Specific Aim 2, we will test this hypothesis by ascertaining extended pedigrees for each variant carrier and correlating genotypes with the presence of AF. The clinical genetic studies will be complemented by experiments in Specific Aim 3 that will determine the electrophysiological consequences of SCN5A variants discovered in AF probands. These studies will use heterologously expressed recombinant human SCN5A sodium channels and patch-clamp recording techniques. Functional characterization of mutations and variants will not only enable validation of their disease-association but also provide insight into pathophysiological mechanisms of AF. The improved understanding of the diverse mechanisms leading to AF represents a first step in the development of subtype-specific therapeutic treatments for this common and morbid condition. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common abnormal heart rhythm (arrhythmia) seen in clinical practice. In this study, we are trying to identify genes that may predispose individuals to developing this arrhythmia. A better understanding of what causes of AF will provide us with new treatments for this common and morbid condition.