Genetics, Mechanisms and Clinical Phenotypes of Arrhythmogenic Cardiomyopathy

描述(由申请人提供)： 致心律失常的室性心肌病(AVC)是一种临床和遗传异质性的心肌疾病，其特征是频繁的、通常威胁生命的心律失常，通常先于心肌结构重构或心力衰竭的临床证据。在大多数有这些遗传性、家族传播性疾病的受试者中，根本原因尚不清楚。AVC包括致心律失常的右室心肌病(ARVC)，最近被描述的致心律失常的左室心肌病(ALVC)，以及一组以心律失常为突出表现的扩张型心肌病(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没有关联，但最近的证据表明，它们具有共同的遗传原因，是相同的“最终共同途径”中断的结果。编码桥粒蛋白或桥粒相互作用蛋白的基因突变似乎是导致ARVC和ALVC的主要原因。最近的证据表明，ALVC和ADCM(因此ARVC)之间存在一些共同的遗传原因，以及编码Z-Disk蛋白的基因突变和ADCM桥粒破坏之间的机制联系。最近，Saffitz和他的同事将细胞生物心肌生物标记物与ARVC和ALVC的遗传和临床/组织病理学结果相关联，并暗示这些发现以及心脏炎症介质的异常是AVCS的诊断。此外，我们还发现，改变β-连环蛋白的化学计量比会损害Wnt信号通路，通过SAP97和ROCK/微管转运机制，阻碍关键蛋白向间盘的正向运输，并激活AvCs中连接细胞损伤和心律失常的凋亡通路。AvCs的原因是由于前向运输的缺陷，关键蛋白(Cx43、NaV1.5、Kir2.1)始终无法定位到插入盘上。然而，尽管在理解经典ARVC的起源和发展方面取得了这些进展，许多问题仍然没有得到解决。首先，只有30-50%的患者发现了致病基因。其次，多重突变(复合突变和双基因杂合性)正作为频繁的关联出现，这增加了对ARVC遗传基础的理解的复杂性。第三，目前的知识不能解释家庭间和家庭内的变异性，这意味着更复杂，可能涉及目前未知的表观遗传和环境因素。第四，由桥粒缺陷引起的ALVC的比例尚不清楚，但其临床鉴定正在增加。第五，考虑到遗传和“最终共同途径”与ALVC的联系，需要做更多的工作来表征ADCM。在这份提案中，我们将把我们以前的ARVC注册拨款(发布为“修订的工作组标准”)中发展的成熟、一致和精确的诊断方法与全面的初级基因分型方法相结合，并使用下一代高通量基因发现技术和生物标记物分析来寻找遗传修饰物，以确定所有形式的AVC(ARVC、ALVC和ADCM)的遗传基础，以建立详细的机制和诊断理解，并将这些发现与临床表型相关联，以改进风险分层和更好的预测 不良事件。我们将检验这一普遍假设，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，导致桥粒的不稳定、间盘的破坏和炎症，并通过改变β-catenin的化学计量比来损害Wnt信号通路。这通过涉及SAP97和岩石/微管运输的机制，损害了关键蛋白质向插入盘的正向运输。它还激活了凋亡通路，从而提供了一种将细胞损伤与动静脉动静脉曲张联系起来的机制。其具体目标是：1)确定导致ARVC、ALVC和ADCM的新基因；2)评估致心律失常性右室心肌病(ARVC)患者的基因-表型相关性；2)评估疑似致心律失常的左室心肌病(ALVC)和扩张型心肌病(ADCM)患者，并评估ALVC和ADCM患者的基因-表型相关性；以及3)发现新的AVC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。 心律失常或其他疾病表现。

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.