SCN5A mutations and dilated cardiomyopathy

描述（由申请人提供）：由SCN5A编码的心脏初级钠通道的打开，负责心肌细胞的快速去极化，启动心脏周期，并成为心脏快速传导的基础。该基因突变与一系列表型相关，包括长QT综合征、Brugada综合征、传导疾病、扩张型心肌病（DCM）和心房颤动。在与这些疾病状态相关的数百种突变中，只有少数与DCM和心力衰竭明确相关，其潜在机制尚不清楚。该建议建立在我们建立钠通道相关疾病小鼠模型的基础上，以验证SCN5A突变通过与电生理功能障碍直接相关的机制启动DCM表型的总体假设；值得注意的是，这将scn5a相关的DCM与其他形式的疾病区分开来。在携带D1275N（一种与人类DCM相关的突变）的小鼠中，我们的主要发现是钠电流峰值降低，门控接近正常，心电图和光学成像显示明显的传导延迟，通道蛋白丰度降低，特别是沿外侧肌细胞边界，以及DCM的年龄依赖性发展。相比之下，其他具有相同或更大的峰值钠电流下降的小鼠系没有表现出传导异常或DCM。因此，在具体目标1中，我们将测试多个相互竞争的假设来解释这一明显的悖论：具体的实验将解决细胞内离子稳态与传导异常的作用，及其潜在的机制，作为DCM表型的发生器。与D1275N不同，DCM相关的R222Q突变在体外表现出惊人的门控变化，患者表现出非常频繁的药物敏感性心室异位活动并发展为DCM。在具体目标2中，我们将对比R222Q和D1275N导致DCM的机制，并验证抑制异位活性改善或逆转DCM表型的假设。在美国，有超过400万人患有心力衰竭，鉴定分子亚群的研究是制定基于机制的治疗方法的重要一步。

DESCRIPTION (provided by applicant): 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.