IN VITRO AND IN VIVO EXPERIMENTAL MODELS FOR INVESTIGATING THE MOLECULAR PATHOGENESIS OF ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a dominant, degenerative cardiomyopathy, frequently involved in sudden death of asymptomatic athletes and teenagers. Human genetic studies over the last few years have offered insight into the potential causes of ARVC. Since mutations causing ARVC have been identified so far in genes encoding desmosomal proteins, such as plakoglobin (JUP), desmoplakin (DSP), plakophilin−2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2), arrhythmogenic right ventricular cardiomyopathy might be considered as “a disease of the desmosome”. Desmosomes are important cell-cell adhesion junctions, predominantly found in the epidermis and heart. In spite of the recent discovery of genes whose mutations cause ARVCs, early molecular events leading to cardiomyocyte degeneration, to fibrosis and to adipose substitution remain elusive. The present project aims at evaluating the pathogenic mechanisms of mutations in DSC2 and DSG2 genes, two ARVC genes recently identified by our group. This will be done both in vitro, by transient transfection of wild-type and mutated cDNA in cultured cardiomyocytes, and in vivo by generation of transgenic and knock-in mouse lines. The phenotypic characterization of the transgenic and knock-in mice will involve electrophysiological, histological and gene expression analyses. The results will lead to identification of cellular mechanisms involved in the molecular pathogenesis of ARVC and, as a consequence, to the isolation of novel ARVC genes, since no causing mutations have been identified in more than 50% of patients. In perspective, such model should prove useful for assessing effects of selected pharmacological treatments for those patients who have already developed this life-threatening disease.