Genetics, Mechanisms and Clinical Phenotypes of Arrhythmogenic Cardiomyopathy

致心律失常性心肌病的遗传学、机制和临床表型

• 批准号: 8920265
• 负责人: FRANK I MARCUS
• 金额: $ 7.97万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-23 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920265
• 关键词: Adverse event; Advisory Committees; Affect; Age of Onset; Apoptotic; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Binding; Bioinformatics; Biological Markers; Cardiac; Cardiomyopathies; Cells; Child; Clinical; Congenital Heart Defects; Connexin 43; DLG1 gene; Data; Databases; Defect; Desmosomes; Diagnostic; Diagnostic Procedure; Diagnostic tests; Dilated Cardiomyopathy; Disease; Disease Progression; Environmental Risk Factor; Epigenetic Process; Event; Failure; Familial disease; Family; Family member; Funding; Future; Gene Mutation; Gene-Modified; Genes; Genetic; Genomics; Genotype; Goals; Grant; Health; Heart failure; Immunohistochemistry; Individual; Inflammation; Inflammation Mediators; Inherited; Intercalated disc; Intercellular Junctions; Knowledge; Lead; Left; Life; Link; Measures; Mutation; Myocardial; Myocardium; Myopathy; National Heart, Lung, and Blood Institute; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Play; Prevention; Preventive; Proteins; Publishing; Registries; Resolution; Resources; Risk; Role; Severity of illness; Signal Pathway; Specimen; Stratification; Sudden Death; Systems Biology; Technology; Testing; Transcript; Variant; Ventricular; Work; base; cell injury; clinical phenotype; cohort; diagnostic accuracy; exome; genetic variant; high throughput technology; improved; next generation; novel; plakoglobin; prevent; repository; stoichiometry; trafficking; treatment strategy

DESCRIPTION (provided by applicant): Arrhythmogenic ventricular cardiomyopathies (AVCs) are clinically and genetically heterogeneous heart muscle disorders characterized by frequent, often life-threatening arrhythmias that typically precede structural remodeling of the heart muscle or clinical evidence of heart failure. In the majority of subjects having these inherited, family transmitted diseases the underlying cause is not known. AVCs include arrhythmogenic RV cardiomyopathy (ARVC), the more recently described arrhythmogenic LV cardiomyopathy (ALVC), and a group of dilated cardiomyopathies in which arrhythmias are prominent (aDCM). While these heart abnormalities may appear unrelated when compared by traditional clinical and pathological criteria, recent evidence indicates they share common genetic causes and result from disruption of the same "final common pathways". Mutations in genes encoding desmosomal proteins or desmosome-interacting proteins appear to play a major role in causing ARVC and ALVC. Recent evidence suggests some common genetic causes between ALVC and aDCM (and therefore ARVC), as well as mechanistic links between mutations in genes encoding Z-disk proteins and desmosomal disruption in aDCM. Recently, Saffitz and colleagues have correlated cell biologic myocardial biomarkers with genetic and clinical/histopathologic findings of ARVC and ALVC and suggests these findings, as well as abnormalities in cardiac inflammatory mediators, are diagnostic of AVCs. In addition, we have shown that Wnt signaling pathways are impaired by changing ?-catenin stoichiometry, impairing forward trafficking of critical proteins to the intercalated disk by mechanisms involving SAP97 and ROCK/ microtubular transport, and activates apoptotic pathways, mechanisms linking cell injury and arrhythmias in AVCs. AVCs result from a consistent failure of critical proteins (Cx43, Nav1.5, Kir2.1) to localize to intercalated disks due to defects in forward trafficking. Despite this progress in understanding the origin and progression of classical ARVC, however, many questions remain unresolved. First, disease-causing genes are identified in only ~30-50 % of patients. Second, multiple mutations (compound and digenic heterozygosity) are emerging as frequent associations, adding more complexity to understanding the genetic basis of ARVC. Third, inter- and intra-familial variability is not explained by current knowledge, suggesting more complexity, potentially involving currently unknown epigenetic and environmental factors. Fourth, the proportion of ALVC due to desmosomal defects is unknown but its clinical identification is increasing. Fifth, much more work needs to be done to characterize aDCM in view of genetic and "final common pathway" links to ALVC. In this proposal we will combine well-established, consistent and precise diagnostic approach developed in our previous ARVC Registry grant (published as the "Modified Task Force Criteria") with a comprehensive primary genotyping approach and search for genetic modifiers using next generation high-throughput genetic discovery technologies and biomarker analysis to identify the genetic basis of all forms of AVCs (ARVC, ALVC, and aDCM), to establish detailed mechanistic and diagnostic understanding, and correlate these findings with clinical phenotypes to improve risk-stratification and better predict adverse events. We will test the general hypothesis that mutations in genes encoding "final common pathway" proteins of the desmosome/cell-cell junction pathway (or its binding partners), leads to destabilization of desmosomes and disruption of the intercalated disk and inflammation, and impairs Wnt signaling pathways by changing the stoichiometry of ?-catenin. This impairs forward trafficking of critical proteins to the intercalated disk by mechanisms involving SAP97 and ROCK/ microtubular transport. It also activates apoptotic pathways, thus providing a mechanism linking cell injury and arrhythmias in AVCs. The Specific Aims are: 1) To identify new genes causing ARVC, ALVC, and aDCM; 2A) To evaluate genotype-phenotype associations in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC); 2B) To evaluate patients with suspected arrhythmogenic left ventricular cardiomyopathy (ALVC) and arrhythmogenic dilated cardiomyopathy (aDCM) and to evaluate genotype-phenotype associations in patients with ALVC and aDCM; and 3) To discover new biomarkers in AVCs and critically assess their value in improving the sensitivity and accuracy of diagnosis and predicting arrhythmias or other manifestations of disease.

描述（由申请人提供）： 致心律失常性室性心肌病 (AVC) 是一种临床和遗传异质性心肌疾病，其特征是频繁且常常危及生命的心律失常，通常先于心肌结构重塑或心力衰竭的临床证据。在大多数患有这些遗传性、家族传播疾病的受试者中，其根本原因尚不清楚。 AVC 包括致心律失常性 RV 心肌病 (ARVC)、最近描述的致心律失常性 LV 心肌病 (ALVC) 和一组以心律失常为主的扩张型心肌病 (aDCM)。虽然与传统的临床和病理标准相比，这些心脏异常可能看起来无关，但最近的证据表明它们具有共同的遗传原因，并且是由于相同的“最终共同途径”被破坏而导致的。编码桥粒蛋白或桥粒相互作用蛋白的基因突变似乎在引起 ARVC 和 ALVC 中发挥着重要作用。最近的证据表明 ALVC 和 aDCM（以及 ARVC）之间存在一些常见的遗传原因，以及编码 Z 盘蛋白的基因突变与 aDCM 桥粒破坏之间的机制联系。最近，Saffitz 及其同事将细胞生物学心肌生物标志物与 ARVC 和 ALVC 的遗传和临床/组织病理学发现相关联，并表明这些发现以及心脏炎症介质的异常可以诊断 AVC。此外，我们还发现，Wnt 信号通路因改变 β-连环蛋白化学计量而受到损害，通过涉及 SAP97 和 ROCK/微管运输的机制损害关键蛋白向闰盘的正向运输，并激活细胞凋亡通路、细胞损伤和心律失常之间的联系机制在 AVC 中。 AVC 是由于前向运输缺陷导致关键蛋白（Cx43、Nav1.5、Kir2.1）始终无法定位到闰盘而导致的。然而，尽管在理解经典 ARVC 的起源和进展方面取得了进展，但许多问题仍未解决。首先，仅在约 30-50% 的患者中鉴定出致病基因。其次，多重突变（复合突变和双基因杂合性）正以频繁的关联形式出现，增加了理解 ARVC 遗传基础的复杂性。第三，目前的知识无法解释家庭间和家庭内的变异性，这表明更加复杂，可能涉及目前未知的表观遗传和环境因素。第四，由于桥粒缺陷导致的 ALVC 的比例尚不清楚，但其临床识别率正在增加。第五，鉴于遗传和与 ALVC 的“最终共同途径”联系，需要做更多的工作来描述 aDCM 的特征。在这项提案中，我们将把我们之前的 ARVC 注册资助（作为“修改后的工作组标准”发布）中开发的完善、一致和精确的诊断方法与全面的初级基因分型方法结合起来，并使用下一代高通量搜索遗传修饰剂基因发现技术和生物标志物分析，以确定所有形式的 AVC（ARVC、ALVC 和 aDCM）的遗传基础，建立详细的机制和诊断理解，并将这些发现与临床相关联表型以改善风险分层并更好地预测 不良事件。我们将测试一般假设，即编码桥粒/细胞-细胞连接途径（或其结合伙伴）的“最终共同途径”蛋白的基因突变，导致桥粒不稳定、闰盘破坏和炎症，并损害 Wnt通过改变β-连环蛋白的化学计量来改变信号通路。这通过涉及 SAP97 和 ROCK/微管运输的机制损害了关键蛋白质向闰盘的正向运输。它还激活细胞凋亡途径，从而提供一种将 AVC 中的细胞损伤和心律失常联系起来的机制。具体目标是： 1) 鉴定导致 ARVC、ALVC 和 aDCM 的新基因； 2A) 评估致心律失常性右心室心肌病（ARVC）患者的基因型-表型关联； 2B) 评估疑似致心律失常性左心室心肌病（ALVC）和致心律失常性扩张型心肌病（aDCM）的患者，并评估 ALVC 和 aDCM 患者的基因型-表型关联； 3) 发现 AVC 中的新生物标志物，并严格评估其在提高诊断和预测的敏感性和准确性方面的价值 心律失常或疾病的其他表现。