Hippo Activation in Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle that affects ≈1 to 2 in 5000 individuals and accounts for 15% to 25% of cases of sudden cardiac death in patients <35 years.1 The cardiomyopathy is characterized by risk for lethal ventricular arrhythmias, ventricular enlargement and dysfunction, and fibro-fatty replacement of cardiomyocytes. Curiously, the disease often disproportionately involves the right ventricle and hence also has been referred to as arrhythmogenic right ventricular cardiomyopathy. Article, see p 454 The molecular genetics of AC indicate that it is a disease of the desmosome, intercellular junctional complexes found in epithelium and in muscle tissue.2 In heart, desmosomes are concentrated at the intercalated discs (IDs) that join the ends of cardiomyocytes. Breakthrough work by McKoy et al3 identified a frameshift mutation in the desmosome protein plakoglobin ( PG , also known as JUP ) as the cause of Naxos disease, a rare, autosomal-recessive form of AC. Subsequently, ≈60% to 65% of more typical autosomal-dominant forms of AC were found to be because of mutations in genes encoding other components of the desmosome, including Plakophilin-2 ( PKP2 ), Desmoglein-2 ( DSG2 ), Desmocollin-2 ( DSC2 ), and Desmoplakin ( DSP ).2 How does disruption of desmosomes lead to ventricular dysfunction, fibro-fatty replacement of myocytes, and a proarrhythmic substrate? Initial studies focused on the structural consequences of weakened intercellular adhesions and disruption of intercellular contacts (Figure). More recent studies also examined the effect that disruption of desmosomes has on intracellular signaling. A common feature of AC mutations is that they diminish PG localization to IDs.4 Indeed, AC mutations cause PG to localize to the nucleus.5 Intriguingly, PG is also known as γ-catenin and has 69% amino acid identity with its better known cousin β-catenin. In addition to participating in intercellular adhesion, β-catenin is also well known for its role as …