Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Inherited Cardiomyopathies

Background:

• Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of myocardial tissue.
• Previous research linked ARVC to mutations in desmosomal genes like DSP and PKP2, suggesting desmosomal defects as a cause.
• Desmoglein-2 (DSG2) is the sole desmoglein isoform in cardiac myocytes, making it a candidate gene for ARVC.

Purpose of the Study:

• To investigate the role of desmoglein-2 (DSG2) gene mutations in patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC).
• To determine the frequency and spectrum of DSG2 mutations in a cohort of ARVC probands.
• To correlate DSG2 mutations with clinical and morphological features of ARVC.

Main Methods:

• Screening of 54 unrelated ARVC probands for DSG2 mutations using denaturing high-performance liquid chromatography and direct sequencing.
• Analysis of mutation types including missense, insertion-deletions, nonsense, and splice site mutations.
• Clinical assessment, endomyocardial biopsy, and electron microscopy in affected individuals.

Main Results:

• Nine heterozygous DSG2 mutations were identified in 8 out of 54 ARVC probands (10%).
• Affected probands exhibited typical ARVC clinical features, often with left ventricular involvement.
• Histopathological findings included myocyte loss, fibrofatty replacement, and desmosomal abnormalities like reduced desmosome number and widened intercellular gaps.

Conclusions:

• This study provides the first evidence of DSG2 gene mutations in a significant proportion of ARVC patients.
• The findings confirm that alterations in desmosome complex genes contribute to ARVC pathogenesis.
• DSG2 mutations are associated with a distinct cardiac phenotype characterized by fibrofatty replacement and desmosomal remodeling.