Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Inherited Cardiomyopathies

Background:

• Arrhythmogenic cardiomyopathy (AC) involves fibro-fatty replacement of heart muscle, causing dangerous arrhythmias.
• Genetic variants in the desmoglein2 (DSG2) gene are implicated in AC, but accurate classification is vital for patient care.
• Distinguishing pathogenic DSG2 variants from benign ones is crucial for effective treatment and family screening.

Purpose of the Study:

• To investigate the pathogenicity of the DSG2 Ser194Leu variant in a patient diagnosed with AC.
• To elucidate the cellular and molecular mechanisms underlying the effects of this specific DSG2 mutation.

Main Methods:

• Whole exome sequencing identified the DSG2 Ser194Leu variant in an AC patient with ventricular tachycardia.
• Electron microscopy and immunohistochemical staining were performed on endomyocardial biopsy samples.

Main Results:

• Electron microscopy revealed widened adhering junctions and disorganized intercalated discs in affected cardiomyocytes.
• Immunohistochemistry showed reduced expression of desmoglein 2 (DSG2) and connexin 43 (CX43) in the proband.
• Reduced DSG2 and CX43 expression and perinuclear accumulation were observed in the proband's cardiac tissue.

Conclusions:

• The DSG2 Ser194Leu variant is classified as a pathogenic missense mutation.
• This mutation is associated with arrhythmogenic left ventricular cardiomyopathy.
• The findings highlight the structural and molecular consequences of DSG2 mutations in AC pathogenesis.