Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy

项目摘要/摘要 确定人类致心律失常性心肌病的新机制 致心律失常的心肌病(AC，又称ARVC)是一种复杂的、通常是潜在致命的疾病 与年轻人的室性心律失常有关。AC是一种遗传性疾病，主要与 心脏桥粒蛋白中的功能丧失基因变异。然而，由于AC疾病的全谱系 基因仍然未知，不幸的是，我们缺乏诊断和治疗该病所必需的关键信息 这种毁灭性的疾病。我们试图确定人类AC的一种新的遗传/分子机制。我们的数据 包括临床、病理学、遗传学、体内、生化和分子研究，支持一种新的和 人类AC背后意想不到的分子机制。具体地说，我们确定了ANK2(编码 AnkB)作为人类AC候选基因。值得注意的是，与大多数AC疾病基因不同，AnkB不是桥粒 蛋白。携带ANK2功能丧失变异的患者表现为AC，导致心源性猝死。一种新的 心脏受限AnkB基因缺失的小鼠模型复制人AC结构重塑， 纤维化和早期死亡率。最后，我们的数据支持心脏AnkB的一种意想不到的机制。 具体地说，我们的数据支持：1)AnkB直接结合β-连环蛋白，这是一种与心脏Wnt紧密相连的分子 2)人ANK2AC和AnkB CKO心脏的β-连环蛋白调节发生改变。我们的 目的探讨人AC中AnkB功能障碍的分子机制。我们的预赛 数据支持AnkB对心脏结构和电功能至关重要的结论，并在 在β-连环蛋白调控中的意外作用。此外，我们的数据支持人类和小鼠的AnkB功能障碍 导致适应不良重塑、心力衰竭、心律失常，并最终导致与改变相关的早期死亡 β-连环蛋白活性。

Project Summary/Abstract Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy Arrhythmogenic cardiomyopathy (AC, also termed ARVC) is a complex and potentially fatal disease commonly associated with ventricular arrhythmias in young adults. AC is an inherited disorder primarily associated with loss-of-function gene variants in cardiac desmosomal proteins. However, as the full spectrum of AC disease genes is still unknown, we unfortunately lack critical information essential for the diagnosis and treatment of this devastating disease. We seek to identify a new genetic/molecular mechanism for human AC. Our data that include clinical, pathological, genetic, in vivo, biochemical, and molecular studies support a new and unexpected molecular mechanism underlying human AC. Specifically, we have identified ANK2 (encodes AnkB) as a human AC candidate gene. Notably, unlike most AC disease genes, AnkB is not a desmosomal protein. Patients harboring ANK2 loss-of-function variants display AC resulting in sudden cardiac death. A new mouse model of cardiac-restricted AnkB deletion phenocopies human AC displaying structural remodeling, fibrosis, and early mortality. Finally, our data support an unanticipated mechanism for cardiac AnkB. Specifically, our data support that: 1) AnkB directly binds β-catenin, a molecule tightly linked with cardiac Wnt signaling in AC, and 2) β-catenin regulation is altered in hearts of human ANK2 AC and AnkB cKO hearts. Our objective is to define the molecular mechanisms underlying AnkB dysfunction in human AC. Our preliminary data support a conclusion that AnkB is critical for cardiac structural and electrical function, and plays an unexpected role in β-catenin regulation. Further, our data supports that AnkB dysfunction in humans and mice results in maladaptive remodeling, heart failure, arrhythmia, and ultimately early death associated with altered β-catenin activity.