Assessing the Significance of Pathogenic Mutations and Autopsy Findings in the Light of 2010 Arrhythmogenic Right Ventricular Cardiomyopathy Diagnostic Criteria

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease associated with significant genotype and phenotype heterogeneity.1 The structural features of ARVC consist of progressive fibrofatty replacement of myocytes and, clinically, the disease has been associated with ventricular arrhythmias at risk of sudden cardiac death.2 Article see p 400 Five of the 8 different genes associated with ARVC encode desmosomal proteins (desmoplakin [DSP], plakophilin-2 [PKP2], desmoglein-2 [DSG2], desmocollin-2 [DSC2], plakoglobin [JUP]) and account for up to 50% of ARVC-unrelated probands. Therefore, ARVC is considered a disease of the desmosome.3 Desmosomes, crucial for normal morphogenesis during all stages of embryogenesis, are found at the intercalated disk subadjacent to adherens junction ensuring mechanical cohesion of cardiomyocytes in the beating heart.4 These multiprotein complexes appear as multilayered, bilaterally symmetrical structures featuring a pair of electron-dense plaques that sandwich an extracellular region of ≈35 nm width. This extracellular space is bisected by a central dense line (dense midline) comprising the desmosomal cadherin ectodomains (DSG2, DSC2). Altogether, >350 mutations have been reported in the 5 putative, causative ARVC desmosomal genes.5 The prevalence of PKP2 mutations among apparently unrelated individuals with ARVC ranges from 11% to 43%, which makes PKP2 the most common gene mutated in ARVC.6,8 PKP2, a member of the armadillo family, links to DSP and to other desmosomal elements via the N-terminal head domain, promoting junction assembly and function. Similar to its adherens junction counterparts (ie, β-catenin), a PKP2 isoform is also present in the nucleus, contributing to the RNA polymerase III holoenzyme complex. The desmosomal protein PKP2 has been shown to interact also with gap junction and ion channel proteins9,10 Disruption of the desmosomal complex could lead to ARVC pathognomonic features by at least 3 different mechanisms: (1) collapse or weakening of desmosomes …