Desmoglein 2–Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function

Abstract

Background— The desmosomal cadherin desmoglein 2 (Dsg2) localizes to the intercalated disc coupling adjacent cardiomyocytes. Desmoglein 2 gene ( DSG2 ) mutations cause arrhythmogenic cardiomyopathy (AC) in human and transgenic mice. AC is characterized by arrhythmia, cardiodilation, cardiomyocyte necrosis with replacement fibrosis, interstitial fibrosis, and intercalated disc dissociation. The genetic DSG2 constellations encountered are compatible with loss of adhesion and altered signaling. To further elucidate pathomechanisms, we examined whether heart-specific Dsg2 depletion triggers cardiomyopathy. Methods and Results— Because DSG2 knockouts die during early embryogenesis, mice were prepared with cardiomyocyte-specific DSG2 ablation. Healthy transgenic animals were born with a functional heart presenting intercalated discs with incorporated desmosomal proteins. Dsg2 protein expression was reduced below 3% in the heart. All animals developed AC during postnatal growth with pronounced chamber dilation, calcifying cardiomyocyte necrosis, aseptic inflammation, interstitial and focal replacement fibrosis, and conduction defects with altered connexin 43 distribution. Electron microscopy revealed absence of desmosome-like structures and regional loss of intercalated disc adhesion. Mice carrying 2 mutant DSG2 alleles coding for Dsg2 lacking part of the adhesive EC1-EC2 domains present an indistinguishable phenotype, which is similar to that observed in human AC patients. Conclusions— The observations show that the presence of Dsg2 is not essential for late heart morphogenesis and for cardiac contractility to support postnatal life. On increasing mechanical demands, heart function is severely compromised as evidenced by the onset of cardiomyopathy with pronounced morphological alterations. We propose that loss of Dsg2 compromises adhesion, and that this is a major pathogenic mechanism in DSG2 -related and probably other desmosome-related ACs.

Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling

“…Several mouse models have been developed for Dsg2 [15, 20–22, 36], Jup [12, 23, 13, 37], Pkp2 [16, 24, 38], Dsp [17] and Des [39] showing either early embryonic lethality or different cardiac pathologies.…”

“…The global knock-out of Dsg 2 is embryonically lethal [15] whereas the cardiac specific knock-out of Dsg2 causes severe cardiomyopathy [22]. In contrast, transgenic mice overexpressing cardiac Dsg2 are without an obvious phenotype [20].…”

“… (A) Cardiac specific knock-out of desmoglein-2 induces severe cardiomyopathy in mice [22]. Desmoglein-2 over-expressing mice are healthy and vital [20].…”

“…However, embryonic lethality caused by global knock-out of Jup [12, 13], Dsp [14], Dsg2 [15] and Pkp2 [16] demonstrated on one hand the general importance of those desmosomal proteins, but limited on the other hand functional analyses in vivo . To circumvent those limitations, several conditional knock-out, knock-in or transgenic mouse models for Dsp [17–19], Dsg2 [20–22], Jup [23] and Pkp2 [16, 24] have been developed, which mimic partially an AC phenotype. In contrast, complete Dsc2 knock-out did not induce a cardiac phenotype in mice under normal housing conditions [25].…”

Proteasome‐mediated proteostasis: Novel medicinal and pharmacological strategies for diseases

“…A separate study on chicken embryos indicates that RBFox3, one of the three isoforms of the RBFox family, is ubiquitinated and degraded in proteasome‐dependent manner, which may further affect the localization and functioning of other isoform RBFox2 . Desmoglein‐2 acts as linker proteins adhering adjacent cardiomyocytes; a missense mutation or cardiac‐specific ablation of this protein is associated with arrhythmogenic cardiomyopathy and familial dilated cardiomyopathy . It was observed that cardiac fibrosis associated protein galectin‐3 plays important roles in stabilizing desmoglein‐2, by interfering with its degradation in proteasome …”