Grant: Operating Grant

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac condition characterized by life threatening heart rhythm disturbances, cardiac arrest or sudden death in young people. The disease affects mainly the right heart and is diagnosed with a wide range of tests that focus on the function and electrical signals of the right ventricle. Genetic testing has identified mutations in at least five different genes, responsible for maintaining cell-cell contacts, causing ARVC in about 50% of patients. The main objective of the proposal is to understand how mutations in those genes lead to the disease. Based on our previous observations in mouse models lacking components of those cellular junctions we propose that alterations in the cell-cell contacts impair mechanical transduction leading to damage of the cell membrane. Thus, membrane repair mechanisms will be activated, but their exhaustion causes at the end heart failure due to fibrosis and necrosis and arrhythmias due to changes in calcium homeostasis. The research program will discover the specific molecular, cellular and genetic mechanisms of a novel mutation (p.Q554X) in a gene called desmocollin-2 which we identified in the Alberta Hutterite population. This mutation appeared to be very common (1/10) and is causing early-onset arrhythmic signs in people who carry two mutant copies of the gene. Besides the mechanistic approach we also aim to characterize clinical features in gene carriers which will help us to identify genetic and environmental factors influencing variability between family members. The new insights gained from this proposed study provides an enormous future perspective for predicting, understanding and may be treating arrhythmias in ARVC and in many other, more common cardiac diseases which frequently recapitulate defects of single gene disorders.