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; 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）： 心律失常性心室心肌病（AVC）在临床和遗传性异质性心肌疾病上是特征的，其特征是频繁，危及生命的心律不齐，通常在心肌或心脏衰竭的临床证据之前进行结构重塑。在大多数具有这些继承的受试者中，家庭传播疾病的根本原因尚不清楚。 AVC包括心律不齐的RV心肌病（ARVC），最近描述的心律失常LV心肌病（ALVC）以及一组心律失常的扩张心律失常（ADCM）。尽管与传统的临床和病理标准进行比较时，这些心脏异常可能似乎无关，但最近的证据表明，它们具有共同的遗传原因，并且由于相同的“最终共同途径”的破坏而导致。编码脱发蛋白或脱骨相互作用蛋白的基因突变似乎在引起ARVC和ALVC方面起着重要作用。最近的证据表明，ALVC和ADCM（以及ARVC）之间的某些常见遗传原因，以及编码Z-磁蛋白的基因突变与ADCM中的脱骨体破坏之间的机械联系。最近，Saffitz及其同事将ARVC和ALVC的遗传和临床/组织病理学发现与遗传和临床/组织病理学发现相关联，并提出这些发现以及心脏炎症介质的异常，是AVC的诊断。此外，我们已经证明了Wnt信号通路会因变化而受损吗？ - 蛋白蛋白stoichiememetry，通过涉及SAP97和Rock/ Microtubular转运的机制，将关键蛋白的前向运输损害了将临界蛋白的前向运输，并激活细胞损伤和AVC中的机制。 AVC是由于关键蛋白（CX43，NAV1.5，KIR2.1）的一致失败而导致的，这是由于正向运输中的缺陷而导致的插入式磁盘。尽管在理解古典ARVC的起源和进展方面取得了这种进步，但是许多问题仍未解决。首先，仅在约30％至50％的患者中鉴定出致病的基因。其次，多个突变（化合物和二元杂合性）是作为频繁的关联而出现的，为理解ARVC的遗传基础增添了更多的复杂性。第三，目前的知识并没有说明更复杂性，可能涉及目前未知的表观遗传和环境因素。第四，由于脱骨缺损而引起的ALVC的比例尚不清楚，但其临床鉴定正在增加。第五，鉴于遗传和“最终共同途径”与ALVC的联系，需要做更多的工作来表征ADCM。在这项提案中，我们将在我们以前的ARVC注册授权（以“修改后的工作组标准”）为基础上开发的良好，一致和精确的诊断方法以及一种全面的主要基因分型方法，并使用下一代高通用遗传学技术和生物标记的所有形式的遗传学基础（ARVC）（ARVC）（ARVC）（ARVC ARVC），使用下一代高通量的遗传学技术和生物标记分析来搜索遗传修饰符机械和诊断理解，并将这些发现与临床表型相关联，以改善风险分层并更好地预测 不利事件。我们将检验以下一般假设：编码脱骨/细胞 - 细胞连接途径的“最终共同途径”蛋白的基因突变（或其结合伴侣），导致脱骨体的破坏并破坏插入的盘和炎症，并通过更改STOICHIENIN的构成wnt信号通道。通过涉及SAP97和岩石/微管转运的机制，这会损害关键蛋白的前临界运输到插入式磁盘上。它还激活凋亡途径，从而提供了将细胞损伤和AVC中心律失常联系起来的机制。具体目的是：1）确定引起ARVC，ALVC和ADCM的新基因； 2A）评估心律失常右心肌病（ARVC）患者的基因型 - 表型关联； 2b）评估疑似心律失常左心室心肌病（ALVC）和心律失常扩张性心肌病（ADCM）的患者，并评估ALVC和ADCM患者的基因型 - 表型关联； 3）在AVC中发现新的生物标志物，并在提高诊断的敏感性和准确性和预测方面进行批判性评估其价值 心律不齐或其他疾病表现。