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Ser194Leu DSG2 mutation, associated with arrhythmogenic left ventricular cardiomyopathy and ventricular tachycardia
Miry Blich1, Yaniv Zohar2, Victoria Cohen-Kaplan3
1Cardiology Division, Rambam Health Care Campus, Haifa, Israel.
Insights
The desmoglein2 (DSG2) Ser194Leu mutation is a pathogenic cause of arrhythmogenic cardiomyopathy (AC). This genetic variant leads to cellular changes, including disrupted intercalated discs, contributing to ventricular arrhythmias.
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.
Introduction:
Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibro-fatty replacement of cardiomyocytes, leading to life-threatening ventricular arrhythmia and heart failure. Pathogenic variants of desmoglein2 gene (DSG2) have been reported as genetic etiologies of AC. In contrast, many reported DSG2 variants are benign or variants of uncertain significance. Correct genetic variant classification is crucial for determining the best medical therapy for the patient and family members.
Methods:
Pathogenicity of the DSG2 Ser194Leu variant that was identified by whole exome sequencing in a patient, who presented with ventricular tachycardia and was diagnosed with AC, was investigated by electron microscopy and immunohistochemical staining of endomyocardial biopsy sample.
Results:
Electron microscopy demonstrated a widened gap in the adhering junction and a less well-organized intercalated disk region in the mutated cardiomyocytes compared to the control. Immunohistochemical staining in the proband diagnosed with AC showed reduced expression of desmoglein 2 and connexin 43 and intercalated disc distortion. Reduced expression of DSG2 and Connexin 43 were observed in cellular cytoplasm and gap junctions. Additionally, we detected perinuclear accumulation of DSG2 and Connexin 43 in the proband sample.
Conclusion:
Ser194Leu is a missense pathogenic mutation of DSG2 gene associated with arrhythmogenic left ventricular cardiomyopathy.
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