Genetic and pathophysiological study of desmin derangements in cardiac disorders

Sammanfattning: Desmin is a chief intermediate filament of skeletal and cardiac muscle. Its main function is to provide structural and functional integrity to the cell and to transmit tension along the myofibrils, protecting them from mechanical stress during contractionrelaxation process. Desmin filaments encircle the Z-bands, link them to each other, to the nuclear membrane and to the cytoplasmic organelles, which make desmin filaments important for intracellular organelle positioning. Desmin has also been implicated in organisation and assembly of sarcomeres during myocyte development and in the process of signal transduction and apoptosis. Aberrations of cytoskeletal proteins and desmin in particular, have been implicated in the development of cardiomyopathies and myopathies. Desmin-related myopathies and cardiomyopathies constitute a heterogeneous group of severe, inherited disorders, which to various extent involve skeletal, cardiac and smooth muscles. The cardiac phenotype may include dilated, hypertrophic and restrictive cardiomyopathies, bundle branch block and A-V conduction block that result in severe heart failure, syncopal episodes and sudden death. Some of these patients need a permanent pacemaker implantation in early childhood. To identify the frequency of desmin mutation in patients with cardiomyopathies a direct sequencing of the desmin gene was performed. Two desmin mutations were identified in patients with dilated cardiomyopathy indicating that desmin gene derangements are not a common cause of cardiomyopathies. One of the described mutations was later proposed to be a rare polymorphism, raising a the question about the possible impact of structural gene polymorphism in the development of cardiac disorders. To elucidate pathophysiologial events underlying desmin cardiomyopathy and myopathy a transgenic mouse model carrying L345P desmin mutations was established using natural a desmin promoter. The desmin transgenic mice (DM) were characterized by moderate morphological alterations of cardiac muscle and cardiac hypertrophy as well as decrease of relative skeletal muscle force. The most striking feature of desmin transgenic mice were ultrastructural mitochondrial changes, namely severe swelling, vacuolization and crysta disruption. The mitochondrial Ca2+ level was significantly increased in cardiac and skeletal myocytes from DM mice compared to wild type, underlying the importance of desmin-mitochondrial interactions in the development of desmin cardiomyopathy\ myopathy. To assess the effects of various desmin mutations on the structural and functional properties of desmin filaments the desmin polymerization process was studied in vitro and in vivo. The study showed that different mutations of the desmin rod domain can compromise desmin polymerization at various stages and different amino acids are critically involved in distinct subunit interactions. However, some mutations do allow assembly to the filament state and still cause phenotype with aggregate formation in humans, suggesting that these mutations could affect interactions not relevant in in vitro conditions and in cultured cells but relevant for tissue homeostasis.