Abstract 1051: Mutant Desmocollin-2 Causes Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart muscle disease characterized by progressive fibrous-fatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal plaque proteins have been previously described to cause both autosomal dominant and autosomal recessive forms of ARVC. Therefore we hypothesized that mutations in the cardiac desmosomal cadherin, desmocollin-2 (DSC2) might cause ARVC in humans. We identified an A to G transition that affects the highly conserved 3′ splice acceptor site of intron 5 (IVS5–2A > G) of the DSC2 gene in a patient with ARVC diagnosed by the proposed Task force criteria. This splice acceptor site mutation in DSC2 led to the use of a cryptic splice acceptor site with a deletion of the highly conserved cell adhesion recognition (CAR) sequence and a creation of a downstream premature termination codon (PTC). Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance (3%) of the truncated mutant allele at mRNA level, supporting possible nonsense-mediated mRNA decay. At protein level the wildype DSC2 expression was reduced when compared with control myocardium, suggesting that haploin-sufficiency may contribute to the disease mechanism for this mutation. To further evaluate the consequences of reduced cardiac DSC2 we cloned the zebrafish dsc2 gene, and studied zebrafish embryos with antisense morpholino knockdown of dsc2. These dsc2 knockdown embryos developed morphologic and hemodynamic features of myocardial contractile failure. Ultrastructural analyses of morphant hearts reveal reduced desmosomal plaque area and consistent loss of the desmosome extracellular electron-dense midlines. We conclude that DSC2 mutations can cause ARVC and demonstrate for the first time in vivo that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis and normal cardiac function. The implication of desmosomal cadherin DSC2 as a new disease gene also extends the concept of ARVC as primarily a disorder of the cardiac desmosome.