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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

基本信息

批准号：
8577488
负责人：
FRANK I MARCUS
金额：
$ 215.65万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/8577488
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 Genetic Variation Genomics Genotype Goals Grant 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 high throughput technology improved next generation novel plakoglobin prevent public health relevance repository stoichiometry trafficking treatment strategy

项目摘要

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）：