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.

Figure 1.

Pedigrees of families A–D and sequence electropherograms of DSC2 showing mutant sequences compared with a normal control. Blackened symbols indicate individuals fulfilling ESC/ISFC diagnostic criteria for ARVD/C and/or those confirmed as affected at postmortem examination; a gray symbol indicates individuals fulfilling the modified diagnostic criteria only; white symbols indicate unaffected individuals; slanted bars indicate deceased individuals; plus (+) and minus (−) signs indicate the presence or absence, respectively, of a mutation in DSC2; an asterisk (*) indicates an individual who declined clinical evaluation and/or genetic testing; squares indicate males; circles indicate females. The index patient in each family is marked with an arrow. A, Family A. Affected individuals carry the M477fsX480 mutation. B, Families B–D. Affected individuals carry the E896fsX900 mutation. In family D, individual II.2 does not fulfill diagnostic criteria, because she has predominantly left ventricular disease.

Figure 2.

Schematic structure of desmocollin-2 (isoform 2a). SP = signal peptide; P = propeptide. The positions of the M477fsX480 and E896fsX900 mutations are marked.