Mutant DSG2 mutations account for approximately 10% of arrhythmogenic cardiomyopathy cases and are characterized by left ventricle involvement, high heart failure risk, and desmosome dysfunction.
This review highlights the specific clinical features and molecular mechanisms of DSG2 mutation-induced arrhythmogenic cardiomyopathy, emphasizing the need for individualized, genotype-based management.
Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition to common clinical and pathological features, ACM caused by mutant DSG2 has specific characteristics, manifesting as left ventricle involvement and a high risk of heart failure. Pathological studies have shown extensive cardiomyocyte necrosis, infiltration of immune cells, and fibrofatty replacement in both ventricles, as well as abnormal desmosome structures in the hearts of humans and mice with mutant DSG2-related ACM. Although desmosome dysfunction is a common pathway in the pathogenesis of mutant DSG2-related ACM, the mechanisms underlying this dysfunction vary among mutations. Desmosome dysfunction induces cardiomyocyte injury, plakoglobin dislocation, and gap junction dysfunction, all of which contribute to the initiation and progression of ACM. Additionally, dysregulated inflammation, overactivation of transforming growth factor-beta-1 signaling and endoplasmic reticulum stress, and cardiac metabolic dysfunction contribute to the pathogenesis of ACM caused by mutant DSG2. These features demonstrate that patients with mutant DSG2-related ACM should be managed individually and precisely based on the genotype and phenotype. Further studies are needed to investigate the underlying mechanisms and to identify novel therapies to reverse or attenuate the progression of ACM caused by mutant DSG2.
Zhang et al. (Sat,) conducted a review in Arrhythmogenic cardiomyopathy. Mutant DSG2 mutations account for approximately 10% of arrhythmogenic cardiomyopathy cases and are characterized by left ventricle involvement, high heart failure risk, and desmosome dysfunction.