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Heart Rhythm. 2010 Oct;7(10):1446-53. doi: 10.1016/j.hrthm.2010.08.007. Epub 2010 Aug 11.

Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy?

Author information

1
Institute of Cardiovascular Science, University College London, United Kingdom. katja.gehmlich@cardiov.ox.ac.uk

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.

PMID:
20708101
PMCID:
PMC2994644
DOI:
10.1016/j.hrthm.2010.08.007
[Indexed for MEDLINE]
Free PMC Article
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