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

Journal article

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.

Authors: Gehmlich, K; Asimaki, A; Cahill, T; Ehler, E; Syrris, P

• Publication status: Published
• Journal: Heart rhythm : the official journal of the Heart Rhythm Society
• Volume: 7
• Issue: 10
• Pages: 1446-1453
• Publication date: 2010-10-01
• DOI: 10.1016/j.hrthm.2010.08.007
• EISSN: 1556-3871
• ISSN: 1547-5271
• Language: English
• Keywords: Pedigree; gamma Catenin; Heart Ventricles; Mutation, Missense; Myocardium; Aged; Arrhythmogenic Right Ventricular Dysplasia; Young Adult; Female; Male; Endocardium; Adolescent; Protein Binding; Adult; Biopsy, Needle; Cadherins; Genotype; Desmoglein 2; Humans; Middle Aged; Plakophilins