Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy?
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2010
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| _version_ | 1826261418736877568 |
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| author | Gehmlich, K Asimaki, A Cahill, T Ehler, E Syrris, P Zachara, E Re, F Avella, A Monserrat, L Saffitz, J McKenna, W |
| author_facet | Gehmlich, K Asimaki, A Cahill, T Ehler, E Syrris, P Zachara, E Re, F Avella, A Monserrat, L Saffitz, J McKenna, W |
| author_sort | Gehmlich, K |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:21:08Z |
| format | Journal article |
| id | oxford-uuid:1a20376a-a75e-487f-9cf7-17f15b9f960c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:21:08Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:1a20376a-a75e-487f-9cf7-17f15b9f960c2022-03-26T10:53:02ZNovel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy?Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1a20376a-a75e-487f-9cf7-17f15b9f960cEnglishSymplectic Elements at Oxford2010Gehmlich, KAsimaki, ACahill, TEhler, ESyrris, PZachara, ERe, FAvella, AMonserrat, LSaffitz, JMcKenna, WBACKGROUND: 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. |
| spellingShingle | Gehmlich, K Asimaki, A Cahill, T Ehler, E Syrris, P Zachara, E Re, F Avella, A Monserrat, L Saffitz, J McKenna, W Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? |
| title | Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? |
| title_full | Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? |
| title_fullStr | Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? |
| title_full_unstemmed | Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? |
| title_short | Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? |
| title_sort | novel missense mutations in exon 15 of desmoglein 2 role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy |
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