Genetic and epigenetic regulation of arrhythmogenic cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is most commonly characterized as a disease of the intercalated disc that promotes abnormal cardiac conduction. Previously, arrhythmogenic cardiomyopathy was frequently referred to as arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D); however, genotype-phenotype studies have defined a broader phenotypic spectrum; with the identification of left-dominant and biventricular subtypes. Molecular insight into AC has primarily focused on mutations in desmosomal proteins and the downstream signaling pathways; however, desmosomal gene mutations can only be identified in approximately 50% of patients with AC. Animal and cellular studies have shown that in addition to abnormal biomechanical properties from changes in desmosome function, crosstalk from the desmosome to the nucleus, gap junctions, and ion channels are implicated in the pathobiology of AC. In this review, we highlight some of the newly identified genetic and epigenetic mechanisms that may lead to the development of AC including the role of the Hippo pathway and microRNAs. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.

Keywords: Arrhythmogenic cardiomyopathy; Desmosome; Hippo; MicroRNA; Single nucleotide polymorphism.

Fig. 1

Schematic of Wnt/β-catenin and Hippo pathways in arrhythmogenic cardriomyopathy. At the intercalated disc, PKCα is localized near the membrane allowing inactivation of NF2 via phosphorylation. YAP phosphorylation state is low and plakoglobin is localized at the ID. Wnt/β-catenin signaling can proceed normally. Disruption of the intercalated disc in AC by a desmosomal mutation effects aberrant signaling via loss of PKCα localization to the submembrane and allowing NF2 activation of the Hippo kinase cascade (including MATS and LATS). Nuclear plakoglobin, perhaps in the form of a complex with β-catenin and YAP, interferes with nuclear β-catenin. β-cat, β-catenin; Dvl, disheveled; LEF, lymphoid enhancer- binding factor-1; NF2, neurofibromin 2; PKCα, protein kinase C-α isoform; TCF, T-cell factor; and TEAD, TEA domain family member 1; YAP, Yes-associated protein.

Fig. 2

Potential mechanisms of microRNA mediated development of arrhythmogenic cardriomyopathy. SNP-associated changes in miRNA target sites located in AC-associated genes 3’UTRs may alter the expression of known proteins implicated in the development of arrhythmogenic cardiomyopathy. Alternatively, changes or mutations in desmosomal proteins may also alter expression of microRNAs important in the development of the myocardial changes seen in arrhythmogenic cardiomyopathy. PKP2, Plakophillin-2; Pkg, Plakoglobin; DSG2, Desmoglein-2; DSC2, Desmocollin-2; miR, microRNA.