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

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy estimated to affect approximately 1 in 5,000 individuals. Cardinal manifestations include right ventricular enlargement and dysfunction, fibrofatty replacement of myocytes in the right ventricle, characteristic electrocardiographic abnormalities, and ventricular arrhythmia most commonly arising from the right ventricle. The disease is frequently familial and typically involves autosomal dominant transmission with low penetrance and variable expressivity. Approximately 50% of symptomatic individuals harbor a mutation in one of the five major components of the cardiac desmosome. Nevertheless, other genetic modifiers and environmental factors complicate the clinical management of mutation carriers as well as counseling of their relatives. This Review summarizes the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, describes possible origins of recurrent mutations, presents theories on the pathogenesis of disease following a mutation, and discusses the current issues surrounding clinical use of genetic analysis in the assessment of individuals with this condition.

Figure 1

The cardiac desmosome and proposed roles of the desmosome in (A) supporting structural stability through cell–cell adhesion, (B) regulating transcription of genes involved in adipogenesis and apoptosis, and maintaining proper electrical conductivity through regulation of (C) gap junctions and (D) calcium homeostasis. Abbreviations: Dsc2, desmocollin-2; Dsg2, desmoglein-2; Dsp, desmoplakin; Pkg, plakoglobin; Pkp2, plakophilin-2; PM, plasma membrane.

Figure 2

Schematic of the five desmosomal proteins in which ARVD/C mutations have been identified and published. Heterozygous mutations are indicated above each diagram and homozygous mutations are indicated below each diagram. (A) Plakoglobin; the 13 armadillo domains are numbered. (B) Desmoplakin; the five N-terminal α-helical bundles (Z, Y, X, W, V) are shown, followed by the rod domain required for dimerization and the A, B, and C subdomains of the plakin-repeat domain. (C) Plakophilin-2; the 10 armadillo domains are numbered. (D) Desmoglein-2 and (E) Desmocollin-2. Abbreviations: DTD, desmoglein-specific terminal domain; EA, extracellular anchor; EC1–4, extracellular domains 1–4; IA, intracellular anchor; ICS, intracellular cadherin segment; IPL, intracellular proline-rich linker; Pro, propeptide; RUD, 6 repeated-unit domains; SS, signal peptide sequence; TM, transmembrane domain.

Figure 3

Tallies of the types of unique mutations found in each of the five desmosomal genes mutated in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Shown are missense, nonsense, and insertion/deletion or frameshift mutations. Abbreviations: DSC2, desmocollin-2; DSG2, desmoglein-2; DSP, desmoplakin; JUP, junctional plakoglobin; PKP2, plakophilin-2.