Molecular mechanisms of the development of cardiomyopathies caused by mutations in desmosomal proteins

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disease leading to ter-minal heart failure and frequently to sudden cardiac death. Molecular genetics revealed that mutations in genes coding for desomsomal proteins are predominately responsible for this dis-ease. Recently, we showed that about 35% of ARVC patients carry sequence variants in the genes (corresponding proteins) DSG2 (desmoglein 2), PKP2 (plakophilin 2), DSP (desmoplakin) and DSC2 (desmocollin 2). We also revealed, that a mutation in the gene DES can cause the phenotype of ARVC. The molecular mechanisms of DES-mutations leading to ARVC are vastly not known.The aims of this project are thereforea) The correlation of pathobiochemical and nanobiophysical properties of DES-mutations asso-ciated with ARVC and their consequences on stability and integrity of the myocardial intermediate filament cytoskeleton and the desmsomal cell adhesion mediated by desmoplakin I. The experiments will focus on atomic force microscopy, single molecule force spectroscopy of desmin filaments.b) The analysis of cytotoxic properties of desmin variants and their degradation by the proteasome or autophagosome/lysosome, respectively.c) It is planned to extend the desmin interaction experiments to intercellular desmosomal systems and perform first nanomechanical experiments (AFM force spectroscopy as well as a single-cell assay with optical tweezers) for investigating the interaction properties of desmoglein-2 variants identified in patients with ARVC.