Novel insights into cardiocutaneous syndromes

A cardiocutaneous syndrome is an overlapping term of rare, inherited and distinct clinical manifestations that affect both the skin and the heart. In the heart, this presents as cardiomyopathy, where the pump function is eventually affected. The skin particularly displays phenotypes like keratoderma, woolly hair and/or alopecia. In severe cases, skin fragility characterized by erosions and blister formation is observed (epidermolysis bullosa simplex). In general, a cardiocutaneous phenotype is primarily caused by pathogenic variants in genes that enable proper cell-cell contacts (desmosomes) and cytoskeletal networks (intermediate filaments). As both the heart and skin are subjected to repetitive, high levels of mechanical stretch (hemodynamic loading of the heart and pressure/rubbing exposure to the skin), typically proteins expressed in both tissues, that provide tissue resilience to sustain these abrasions are affected in patients with a cardiocutaneous syndrome. In part 1 of this thesis we observed that a dose-dependent disease severity is common in patients with desmoplakin mutations and gained insight into the effects of mechanical loading on several patient-derived keratinocytes and engineered heart tissues. In part 2 of this thesis we unraveled the underlying mechanism by which mutations in KLHL24 cause cardiomyopathy in patients. We also performed two rescue experiments that prevented the phenotype in patient-derived engineered heart tissues.