Abstract 10843: Mutated Desmoglein-2 Proteins in Arrhythmogenic Right Ventricular Cardiomyopathy are Incorporated into the Desmosome and Exhibit Dominant-negative Effects
Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The majority of ARVC patients carry mutations in genes encoding desmosomal proteins, which are expressed in both myocardium and epidermis. This study aimed to investigate how mutations in the desmoglein-2 (DSG2) gene contribute to the pathogenesis of ARVC.
Methods and Results: Mutation analysis of 5 ARVC-related desmosomal genes in 71 index patients identified 3 recognized DSG2 mutations in 12 families. For the first time a family with recessive ARVC caused by a DSG2-p.T335A missense mutation was identified. In the remaining families, heterozygous mutation carriers had a variable disease expression while individuals carrying additional rare desmosomal missense variants were fully penetrant. Since desmosomal proteins are expressed in skin tissue, keratinocytes served as a cell model to investigate DSG2 expression by Western blotting, protein mass spectrometry, and 2-dimensional polyacrylamide gel electrophoresis. The results showed that heterozygous mutation carriers expressed both mutated and wild type DSG2 proteins. These findings were consistent with the results obtained by immunohistochemistry of endomyocardial biopsies and epidermal tissue of mutation carriers, which demonstrated a normal expression pattern of DSG2.
Conclusion: All mutated DSG2 proteins were incorporated into desmosomes, which was consistent with a dominant-negative effect of the mutations. Homozygous or compound heterozygous mutation carriers were fully penetrant, while family members carrying only 1 mutation exhibited incomplete penetrance. This indicated a gene-dosage effect and suggested that ARVC caused by DSG2 mutations are often transmitted by recessive or digenic inheritance.
- © 2012 by American Heart Association, Inc.