Mutant Desmocollin-2 Causes Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor-site mutation in intron 5 (c.631-2A-->G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.

Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

“…51,52 Mutations in the desmocollin-2 gene (DSC2) seem to be infrequent in ARVD/C; only five DSC2 mutations have been described to date (summarized in Figure 2E). [51][52][53] Although Dsc2 targeting in the mouse has not yet been reported, zebrafish treated with dsc2 antisense morpholino oligos demonstrated bradycardia, impaired contractility and chamber dilation. 51…”

Recurrent and founder mutations in the Netherlands

“…ARVC/D is familial in up to 50% of cases. 1,[8][9][10][11][12] Since the identification of mutations in the genes encoding the desmosomal proteins desmoplakin (DSP) 13 and plakophilin-2 (PKP2), [14][15][16][17] followed by mutations in desmocollin-2 (DSC2), 18 desmoglein-2 (DSG2) 19 and plakoglobin (JUP), 20 it has been recognised that ARVC/D is mainly a disorder of the cardiac desmosome (figure 2), a cell adhesion complex residing in the intercalated disk of cardiomyocytes. Comprehensive screening of these genes encoding the proteins of this complex leads to the identification of a pathogenic mutation in approximately 40 to 60% of ARVC/D patients.…”

The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy

“…Five of them encode major desmosomal proteins: plakoglobin (MIM *173325), 3,4 desmoplakin (MIM *125647), 5 plakophilin-2 (MIM *602861), 6 desmoglein-2 (MIM *125671) 7 and desmocollin-2 (MIM *125645). 8,9 The involvement of such genes led to the current idea that ARVC/D is a disorder caused mainly by defects in cell-cell adhesion.…”

“…12 To date, five different DSC2 mutations have been reported: two frameshift mutations p.M477fsX480 and p. E896fsX900, 8 a heterozygous splice acceptor site mutation c.631-2A4G 9 and two missense mutations p.E102K and p.I345T. 13 In vitro functional studies showed that the two point mutations affect the intracellular localisation of DSC2a, thus suggesting a potential pathogenic effect.…”