Grant: Emerging Team Grant: From Genes to Proteins, Cells, Tissues and Patients - LOI

The application represents a unique opportunity to capitalize on a Canadian discovery of the TMEM43 gene causing an autosomal dominant form of sudden cardiac death in 15 multiplex ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia type-5) families from the Newfoundland founder population in the lab of the nominated Principal Investigator (Merner, et al, 2008; US patent pending). This is the first association of the TMEM43 gene with human disease and the most significant discovery in ARVC research in recent years. The first ARVC gene (plakoglobin) was isolated in 2001 in an autosomal recessive form of ARVC (Naxos disease). Plakoglobin is a desmosomal protein, and this finding directed future functional candidate approaches so that subsequent ARVC genes encode desmosomal proteins. This "looking under the lamppost" approach has limited our view of ARVC and cardiomyopathies in general. The TMEM43 gene (ARVD5) represents an opportunity for a broader exploration as the protein has no homology to desmosomal proteins and may function upstream of a final common pathway. ARVC is a well recognized condition and an important cause of morbidity and mortality. In particular ARVC is a significant cause of sudden cardiac death especially among young people. Of late it has been recognized that this condition can result from different genetic mutations in multiple genes. Unfortunately, the clinical diagnosis of this condition is difficult. Currently published Task Force criteria are employed as the "gold standard". However it is likely that this condition has both a "concealed" phase followed by a more "manifest" phase when typical clinical tests begin to demonstrate abnormality. Unfortunately during the "concealed" phase when there is very little macroscopic structural cardiac abnormality lethal ventricular arrhythmia may occur. This observation demonstrates the direct clinical impact improved diagnostic mechanisms will have on patients with ARVC.