MOLECULAR PATHOGENESIS OF CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) LINKED TO CALSEQUESTRIN 2 (CASQ2) MUTATIONS

The current proposal focuses on the investigation of the mechanisms of one of the diseases causing sudden cardiac death in young individuals, i.e., catecholaminergic polymorphic ventricular tachycardia (CPVT).Our main objective is to define the cellular dysfunction developing in the heart of patients who carry mutations in the cardiac calsequestrin gene (CASQ2). The protein encoded by this gene acts as an intracellular buffer for calcium (Ca) ions that are pivotal players in the development of cardiac contraction and of the cardiac action potential. Patients with mutations in the CASQ2 gene develop potentially lethal cardiac arrhythmias as a consequence of stress or emotions that induce excessive release of Ca from intracellular stores. Our aim is pursued through a synergistic interaction between a leading clinical and molecular group with expertise in the diagnosis and management of patients with CPVT and in the investigation of the molecular mechanisms of the disease, and a group of basic scientists who are leaders in the study of the physiology of CSQ and of the regulation of intracellular Ca. Specifically we intend to investigate the pathophysiology of CPVT using a multifaceted approach spanning from clinical evaluation to basic research. We plan to pursue our goal by: 1) performing molecular screening to identify CASQ2 mutations in CPVT patients and correlate mutations to the clinical phenotype; 2) performing in vitro functional studies of CASQ2 mutations, e.g., Ca binding properties, intracellular trafficking; 3) developing mice models carrying defective CASQ2 to study the mechanisms of onset of arrhythmias.In summary, our goal is to establish a global research strategy for CPVT aimed at: 1) the definition of the epidemiological, genetic and pathophysiological profile of the CASQ2 related variant of this disease, and 2) the development of novel risk stratification schemes and therapeutic strategies.