Positional Cloning and Candidate Gene Approach to Familial Atrial Fibrilation

摘要 心房颤动（房颤）是临床上最常见的心律失常，已达到流行病的程度 在美国老龄化人口中的比例。大多数AF继发于其他疾病，但高达30%的患者 没有明显的原因，据说患有“孤立性”或特发性房颤。我们和其他人已经证明， 孤立性AF具有相当大遗传成分，并已表明孤立性AF在表型和遗传上 异质性紊乱因此，越来越多的人认识到， AF，实际上已经描述了许多遗传基因座。此外，基因编码的突变 心脏钾通道和缝隙连接已在孤立病例和小kindrance中报道。而 存在遗传形式的AF，表型复杂性限制了确定突变携带者的努力， 找出致病基因。在一个大的AF家族中，我们已经用一个新的基因定位了5号染色体上的AF基因座。 延长的信号平均P波持续时间作为AF的中间或内在表型。在特定目标1中， 我们建议在5p15基因座上鉴定出引起单独房颤的基因，并评估其对房颤的贡献。 家族性、散发性和典型AF患者的大队列。 负责心脏动作电位的快速去极化上行，并且是 抗心律失常药物，其中一些可有效治疗房性心律失常。越来越多的证据 支持SCN 5A（编码人类心脏钠通道的基因）在AF中的作用。 SCN 5A与室性心律失常（先天性长QT间期）的遗传易感性有关 综合征和Brugada综合征）、心脏传导受损或这些表型的组合。一些 这些综合征包括AF，SCN5A突变最近也与家族性扩张性房颤有关。 心肌病和房性心律失常。因此，我们对375名房颤患者的基因进行了重新测序，其中包括118名 在SCN5A的变异体中发现了19个罕见的错义变异体，包括22个新的等位基因 先证者（5.9%）。我们假设这些基因变异中的一些是房颤易感性的原因。在 具体目标2，我们将通过确定每个变异携带者的扩展谱系来检验这一假设， 将基因型与AF的存在相关联。临床遗传学研究将得到补充， 特定目标3中的实验，将确定SCN 5A变体的电生理学后果 在AF先证者中发现。这些研究将使用异源表达的重组人SCN 5A 钠通道和膜片钳记录技术。突变和变体的功能表征 不仅能够验证其疾病相关性，而且还提供了对病理生理学的深入了解。 AF的机制。对导致AF的不同机制的理解的提高代表了第一个 这是发展针对这种常见和病态疾病的亚型特异性治疗方法的一步。

Abstract 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.