Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Abstract

SUMMARYArrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy estimated to affect approximately 1 in 5,000 individuals. Cardinal manifestations include right ventricular enlargement and dysfunction, fibrofatty replacement of myocytes in the right ventricle, characteristic electrocardiographic abnormalities, and ventricular arrhythmia most commonly arising from the right ventricle. The disease is frequently familial and typically involves autosomal dominant transmission with low penetrance and variable expressivity. Approximately 50% of symptomatic individuals harbor a mutation in one of the five major components of the cardiac desmosome. Nevertheless, other genetic modifiers and environmental factors complicate the clinical management of mutation carriers as well as counseling of their relatives. This Review summarizes the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, describes possible origins of recurrent mutations, presents theories on the pathogenesis of disease following a mutation, and discusses the current issues surrounding clinical use of genetic analysis in the assessment of individuals with this condition.

Characterization of HACD1 K64Q mutant found in arrhythmogenic right ventricular dysplasia patients

“…Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited heart disease characterized by a gradual loss of right ventricular myocardium and fibro-fatty infiltration with a prevalence of 1 in 2,500 to 1 in 5,000 (1,2). It is a major cause of sudden death in young people and athletes (1,2).…”

“…It is a major cause of sudden death in young people and athletes (1,2). To date, eight genes have been identified as being associated with ARVD: the DSP gene encoding desmoplaskin, PKP2 encoding plakophilin 2, DSC2 encoding desmocollin 2, DSG2 encoding desmoglein 2, JUP encoding plakoglobin, TGFB3 encoding transforming growth factor β3, TMEM43 encoding transmembrane protein 43, and TP63 encoding tumor protein 63 (3).…”

“…To date, eight genes have been identified as being associated with ARVD: the DSP gene encoding desmoplaskin, PKP2 encoding plakophilin 2, DSC2 encoding desmocollin 2, DSG2 encoding desmoglein 2, JUP encoding plakoglobin, TGFB3 encoding transforming growth factor β3, TMEM43 encoding transmembrane protein 43, and TP63 encoding tumor protein 63 (3). Most of these ARVD-causing mutations are autosomal dominant, although some autosomal recessive mutations have also been identified (2). Five of the ARVD genes encode desmosomal proteins (desmoplaskin, plakophilin 2, desmocollin 2, desmoglein 2, and plakoglobin) (1)(2)(3).…”

Special issue Heidelberg Heart II: Abstracts of oral and poster presentations

“…In addition, CD44+/CD45+ cells are involved in the acute and chronic phases of the cardiomyopathy. and also in dilated cardiomyopathy (DCM), which are both characterized by fibrosis and arrhythmia (Awad et al 2008;Posch et al 2008;Basso et al 2008;Marcus et al 2010). To investigate the pathomechanism of desmosome-related cardiomyopathy, we developed mice carrying a deletion in the extracellular domains of the desmosomal cadherin desmoglein 2 (Dsg2).…”

Comparison of radionuclide angiographic synchrony analysis to echocardiography and magnetic resonance imaging for the diagnosis of arrhythmogenic right ventricular cardiomyopathy

“…1 Affected patients suffer from heart failure, malignant ventricular arrhythmias, and sudden cardiac death. 2 Accurate diagnosis and discernment from benign disorders, particularly idiopathic right ventricular outflow tract ventricular tachycardia (RVOT VT), is critical to guide appropriate clinical care, given the high risk of sudden death.…”