Study of the molecular pathogenesis of arrhythmogenic cardiomyopathy due to Desmoglein-2 mutations: the zebrafish helps the mouse

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a progressively degenerative cardiomyopathy, frequently involved in juvenile sudden death. ARVC is considered a disease of cell adhesion because mutations in desmosomal genes have been involved in the pathogenesis of ARVC in a significant proportion of patients. To identify the molecular pathogenic mechanisms involved in ARVC, we have generated cardiac-restricted desmoglein-2 (DSG2) transgenic mice. All the transgenic lines expressing human mutated DSG2 (G100R, N266S, Q558X) resemble the clinical features of ARVC. At molecular level, we checked the expression and localization of some adhesion proteins, demonstrating changes in expression and localization of beta-catenin in hearts of transgenic mice carrying the mutated proteins. To establish whether the observed increase in beta-catenin expression has a possible direct effect on Wnt signaling, we co-injected in zebrafish embryos the WT and mutated DSG2 mRNAs with BAT-lux reporter plasmids containing the luciferase enzyme cDNA under the control of the responsive elements of Wnt/beta-catenin signaling. Luciferase reporter activity resulted significantly higher in fishes injected with mutant constructs compared with those injected with wild type. To further examine the relationship of beta-catenin and Wnt signaling, we co-injected dickkopf-1 (Dkk1), an inhibitor of Wnt signalling, and we showed that Dkk1 rescued the phenotype in embryos. In conclusion, mutations in desmosomal proteins can perturb the normal balance of critical proteins in junctions and the citosol which, in turn, could alter gene expression by circumventing normal Wnt signaling pathway.