G790del mutation in DSC2 alone is insufficient to develop the pathogenesis of ARVC in a mouse model

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Inherited Cardiac Diseases

Background:

• Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart condition linked to desmosomal gene mutations, potentially causing heart failure or sudden cardiac death.
• Mutations in the DSC2 gene are implicated in ARVC, accounting for approximately 2% of genetic causes.
• The specific G790del mutation in DSC2 warrants investigation into its role in ARVC pathogenesis and cardiac function.

Purpose of the Study:

• To investigate the impact of the G790del mutation in the DSC2 gene on the arrhythmogenic mechanisms and overall cardiac function.
• To establish a mouse model for studying the G790del DSC2 mutation's effects.

Main Methods:

• Generation and analysis of heterozygous (+/G790del) and homozygous (G790del/G790del) DSC2 mutant mice.
• Assessment of right ventricular (RV) and left ventricular (LV) structure and function.
• Evaluation of cardiomyocyte contractility and intracellular calcium handling.

Main Results:

• Neither heterozygous nor homozygous G790del mice exhibited RV structural/functional defects or lethal arrhythmias.
• Homozygous G790del mice showed mild LV dysfunction by 6 months of age.
• Isolated cardiomyocytes from homozygous mice displayed reduced cell shortening and prolonged calcium transients, with increased spontaneous calcium transients upon isoproterenol stimulation.

Conclusions:

• The G790del mutation in DSC2 is not directly implicated in the pathogenesis of ARVC.
• This mutation is associated with subtle left ventricular contractile dysfunction.
• Calcium handling abnormalities in the left ventricle are observed in the presence of the G790del DSC2 mutation.