SCN5A mutations and dilated cardiomyopathy

SCN5A突变与扩张型心肌病 摘要 由SCN5A编码的初级心脏钠通道的开放负责快速的心肌细胞 启动心脏循环的去极化，是心脏快速传导的基础。该基因的突变 与一系列表型有关，包括长QT综合征，Brugada综合征， 传导性疾病、扩张型心肌病(DCM)和心房颤动。数以百计的突变与 这些疾病状态，只有少数明显与扩张型心肌炎和心力衰竭有关，而 潜在的机制还不清楚。这一建议建立在我们建立小鼠模型的基础上 钠通道相关疾病，以检验SCN5A突变启动DCM的总体假设 通过与电生理功能障碍直接相关的机制表现型；值得注意的是，这区分了 SCN5A相关的扩张性心肌病与其他形式的疾病。在携带D1275N的小鼠中，与 人类DCM，我们的主要发现是峰值钠电流降低，接近正常门控，显著传导 由于心电图和光学标测的延迟，通道蛋白的丰度降低，特别是沿外侧 心肌细胞边界与扩张型心肌病年龄相关性发展。相比之下，其他鼠标行具有相同的或 钠电流峰值下降幅度较大时，不会出现传导异常或DCM。因此，在 具体目标1，我们将测试多个相互竞争的假设来解释这一明显的悖论：具体 实验将解决细胞内离子稳态与传导异常的作用，以及 其潜在的机制，作为DCM表型的生成者。与D1275N不同，与DCM关联的 R222Q突变在体外表现出显著的门控变化，患者对药物非常敏感 室性异位活动和发展为扩张型心肌病。在具体目标2中，我们将对比R222Q 和D1275N引起DCM并检验抑制异位活动改善或逆转DCM的假说 DCM表型。心力衰竭在美国影响着400多万人，研究发现 分子亚集代表了定制基于机制的治疗的重要一步。

SCN5A mutations and dilated cardiomyopathy ABSTRACT Opening of the primary cardiac sodium channel, encoded by SCN5A, is responsible for rapid myocyte depolarization that initiates the cardiac cycle and underlies fast conduction in the heart. Mutations in the gene have been associated with a range of phenotypes, including long QT syndrome, Brugada syndrome, conduction disease, dilated cardiomyopathy (DCM) and atrial fibrillation. Out of hundreds of mutations linked to these disease states, only a handful have been clearly associated with DCM and heart failure and the underlying mechanisms are not understood. This proposal builds on our work establishing murine models of sodium channel-related disease to test the overall hypothesis that SCN5A mutations initiate the DCM phenotype through mechanisms directly related to electrophysiologic dysfunction; notably, this distinguishes SCN5A-related DCM from other forms of the disease. In mice with D1275N, a mutation associated with human DCM, our major findings are decreased peak sodium current, near normal gating, striking conduction delay by ECG and optical mapping, decreased abundance of the channel protein especially along the lateral myocyte border, and age-dependent development of DCM. By contrast, other mouse lines with equivalent or greater decreases in peak sodium current do not display conduction abnormalities or DCM. Accordingly, in Specific Aim 1, we will test multiple competing hypotheses to explain this apparent paradox: specific experiments will address the roles of intracellular ionic homeostasis versus abnormalities in conduction, and their underlying mechanisms, as generators of the DCM phenotype. Unlike D1275N, the DCM-associated R222Q mutation displays striking gating changes in vitro and patients display very frequent drug-sensitive ventricular ectopic activity and develop DCM. In Specific Aim 2, we will contrast mechanisms whereby R222Q and D1275N cause DCM and test the hypothesis that suppression of ectopic activity improves or reverses the DCM phenotype. Heart failure affects more that 4 million people in the United States and studies to identify molecular subsets represent an important step to tailoring mechanism-based therapy.