期刊
HEART RHYTHM
卷 7, 期 10, 页码 1446-1453出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2010.08.007
关键词
Arrhythmogenic right ventricular cardiomyopathy; Desmoglein-2; Desmosome; Genetics; Missense mutation; Plakophilin-2
资金
- British Heart Foundation [RG/04/010]
- Heart Rhythm Society
- National Institutes of Health [HL102361]
- Department of Health's National Institute for Health Research Biomedical Research Centre
- MRC [G0400153] Funding Source: UKRI
- Medical Research Council [G0400153] Funding Source: researchfish
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.
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