Abstract 3401: Mutations in Desmocollin2 Gene Associated with Arrhythmogenic Right Ventricular Cardiomyopathy
Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease characterized by progressive myocyte loss, fibro-fatty replacement of right ventricular myocardium, left bundle branch block pattern arrhythmias and risk of sudden death. Mutations in five genes including three which encode desmosomal proteins (desmoplakin, plakophilin-2 and desmoglein-2) have been identified so far in patients affected with autosomal dominant ARVC. We hypothesized that mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac myocytes, may account for ARVC.
Methods: Eighty ARVC probands were screened for mutations in the coding region of DSC2 gene. Denaturing high-performance liquid chromatography (DHPLC) and direct sequencing were applied. In order to establish the effect of identified DSC2 variants, mutant DSC2 cDNAs were expressed by transient transfection of desmosome-forming rodent cell lines.
Results: Three DSC2 variants (E102K, I345T and 631–10C>T) have been identified in 3 out of 80 (4%) ARVC index cases. The three patients, showing a severe form of the disease, were negative for mutations in coding sequences of other genes involved in ARVC. None of the detected nucleotide changes was found in a control group of 250 healthy and unrelated subjects (500 control chromosomes) of Italian origin. We investigated the effect of the missense mutations on the intracellular distribution of DSC2 protein. Wild-type DSC2a-GFP was detected almost exclusively to the cell membrane at cell-cell interfaces, while both E102K and I345T DSC2-GFP were detected almost exclusively in the cytoplasm, thus suggesting that these mutant DSC2 products are no longer targeted to cell membrane or desmosomes in vitro.
Conclusion: Based upon the above data, we suggest that mutations at DSC2 determine ARVC. Therefore, we confirm that ARVC is mostly due to genetic alterations of the desmosomal complex.