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Novel missense mutations in exon 15 of desmoglein-2: Role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy?
- Source :
- Heart Rhythm; Oct2010, Vol. 7 Issue 10, p1446-1453, 8p
- Publication Year :
- 2010
-
Abstract
- Background: The diagnosis of arrhythmogenic right ventricular cardiomyopathy can be challenging. Disease-causing mutations in desmosomal genes have been identified. A novel diagnostic feature, loss of immunoreactivity for plakoglobin from the intercalated disks, recently was proposed. Objective: The purpose of this study was to identify two novel mutations in the intracellular cadherin segment of desmoglein-2 (G812S and C813R in exon 15). Co-segregation of the G812S mutation with disease expression was established in a large Caucasian family. Endomyocardial biopsies of two individuals showed reduced plakoglobin signal at the intercalated disk. Methods: To understand the pathologic changes occurring in the diseased myocardium, functional studies on three mutations in exon 15 of desmoglein-2 (G812C, G812S, C813R) were performed. Results: Localization studies failed to detect any differences in targeting or stability of the mutant proteins, suggesting that they act via a dominant negative mechanism. Binding assays were performed to probe for altered binding affinities toward other desmosomal proteins, such as plakoglobin and plakophilin-2. Although no differences were observed for the mutated proteins in comparison to wild-type desmoglein-2, binding to plakophilin-2 depended on the expression system (i.e., bacterial vs mammalian protein expression). In addition, abnormal migration of the C813R mutant protein was observed in gel electrophoresis. Conclusion: Loss of plakoglobin immunoreactivity from the intercalated disks appears to be the endpoint of complex pathologic changes, and our functional data suggest that yet unknown posttranslational modifications of desmoglein-2 might be involved. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15475271
- Volume :
- 7
- Issue :
- 10
- Database :
- Supplemental Index
- Journal :
- Heart Rhythm
- Publication Type :
- Academic Journal
- Accession number :
- 53970513
- Full Text :
- https://doi.org/10.1016/j.hrthm.2010.08.007