Mutations of cardiac calsequestrin and cardiac arrhythmias: novel insights on pathogenesis and therapy

Genetically determined sudden death strikes subjects during pediatric age and youth, often without warning symptoms. In the past 15 years, thanks to the contribution of several studies and research groups a number of genes that may cause the electrical instability of the heart and predispose to sudden death have been discovered; the identified genetic defects in combination with environmental triggering factors (frequently including physical activity), cause the onset of severe alterations to the cardiac rhythm that if not readily treated lead to cardiac arrest and death within minutes. Thanks to financial support of Telethon, our laboratory has contributed to these studies, with the discovery of some of the disease-causing genes, with the creation of epidemiological registers, and experimental models (cellular and animal) for these diseases. This research project is focused on a genetic disease, Catecholaminergic ventricular tachycardia (CPVT) which causes serious arrhythmias and sudden death during intense physical activity or emotion. If not properly treated approximately 60% of patients with CPVT experience at least one episode of potentially lethal arrhythmia within 40 years of age. In particular, we will address CASQ2 gene mutations that cause the autosomal recessive variant of the disease. In the three-year duration of the project we propose to conduct detailed studies on the mechanisms of the disease and to develop experimental models to rescue in vitro and in vivo the susceptibility to arrhythmias. In particular, we will produce vectors to transfer to the interior of cardiac cells healthy gene. Through experimental studies on transgenic mice we will aim at providing the proof of principle that effective correction of the phenotype in this disease is feasible.