Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated with Mutations in the Desmosomal Gene Desmocollin-2

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited myocardial disorder associated with arrhythmias, heart failure, and sudden death. To date, mutations in four genes encoding major desmosomal proteins (plakoglobin, desmoplakin, plakophilin-2, and desmoglein-2) have been implicated in the pathogenesis of ARVD/C. We screened 77 probands with ARVD/C for mutations in desmocollin-2 (DSC2), a gene coding for a desmosomal cadherin. Two heterozygous mutations--a deletion and an insertion--were identified in four probands. Both mutations result in frameshifts and premature truncation of the desmocollin-2 protein. For the first time, we have identified mutations in desmocollin-2 in patients with ARVD/C, a finding that is consistent with the hypothesis that ARVD/C is a disease of the desmosome.

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

“…Different haplotypes segregated with the p.A897KfsX4 variation in each of the five Italian patients showing the absence of a founder effect for this variation (data not shown). This result confirms data reported by Syrris et al 8 for their three families, suggesting that p.A897KfsX4 is a recurrent variation.…”

“…The frameshift variation p.A897KfsX4, primarily reported as p.E896fsX900 by Syrris et al, 8 causes a premature termination of the protein. Only the last five amino acids of DSC2a were altered: three were changed and the last two were lost ( Figure 1b Five unrelated ARVC/D index cases (allele frequency 2.2%) were found to carry the p.A897KfsX4 variation, as well as 6 out of 200 control subjects (allele frequency 1.5%).…”

“…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.…”

Arrhythmogenic Cardiomyopathy

“…To-date, 11 disease genes have been linked to the AC phenotype, highlighting genetic heterogeneity. Most of mutations in dominant forms have been identified in desmosomal genes including DSP, plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and JUP [43,[46][47][48][49][50] (Table 3). Only isolated reports showed causal mutations in non-desmosomal genes, such as transmembrane protein 43 (TMEM43), desmin (DES), titin (TTN), Lamin A/C (LMNA), phospholamban (PLN) and αT-catenin (CTNNA3), sometimes with a clinical phenotype similar but not identical to AC, as to be considered phenocopies or overlap syndromes [51][52][53][54][55][56].…”