A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy

Familial Dilated Cardiomyopathy (FDCM) is caused by mutations in genes encoding myocardial force transduction proteins. Desmoglein-2 (DSG2) and Desmocollin-2 (DSC2) provide cellular adhesion and force transduction by cell-to-cell anchorage. To test whether perturbations of DSG2 or DSC2 exhibit a pathogenic impact on DCM pathogenesis, we sequenced both genes in 73 patients with FDCM and assessed prevalence of missense variations in matched control cohorts. We detected two missense variations in DSG2 (V55M and V919G) which were absent in 360 control alleles. Surprisingly, both variants were previously reported in patients with arrhythmogenic right ventricular cardiomyopathy. Yet, in the present study only the DSG2-V55M variant showed segregation with DCM in a family pedigree. Subsequent, analysis of 538 patients with idiopathic DCM and 617 consecutive control individuals resulted in identification of thirteen DSG2-V55M carriers with DCM, whereas only three control subjects harbored the variant. DSG2 immunostaining revealed pale structures of the intercalated disc in myocardium of one unique homozygous DSG2-V55M carrier. Furthermore, myocardial desmosomal structures were significantly shortened when compared to DCM myocardium negative for DSG2-V55M. Thus, our study identified the DSG2-V55M polymorphism as a novel risk variant for DCM associated with shortened desmosomes of the cardiac intercalated disc.