Asimaki, A.;
(2008)
Arrhythmogenic right ventricular cardiomyopathy, a disease of the desmosome; genetic and functional studies.
Doctoral thesis , University of London.
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Abstract
Mutation analysis of the recognized ARVC genes and of further candidate genes was performed on a large cohort of ARVC patients. Several novel mutations were identified and three further desmosomal genes were linked to the disease: plakophilin2, desmocollin2 and desmoglein2. Heart and skin samples from ARVC patients were subjected to microscopic examination and immunohistochemistry to study the effect of the newly-identified mutations on the structure of cell adhesion complexes.;The functional effects of a particular novel mutation were thoroughly examined in vitro. S39_K40insS is the first dominant ARVC-causing plakoglobin mutation to be reported. Yeast-two hybrid analysis was used to investigate the effect of S39_K40insS on the proteins interactions established by plakoglobin. A HEK293 cell line stably expressing the mutant protein was generated and used to study the effects of S39_K40insS on desmosomal structure, cell proliferation, cell death, subcellular localization and expression levels of proteins involved in adhesion and signalling and cellular responses to defined mechanical load. A recombinant adenovirus expressing the mutant protein was generated and used to transfect neonatal rat ventricular cardiomyocytes, whose behaviour and responses were subsequently analysed. The functional consequences of S39_K40insS were compared with those of PK215del2, a previously reported recessive plakoglobin mutation known to underlie Naxos disease, a syndromic form of ARVC.;These results point towards novel mechanisms of disease pathogenesis, that apart from weakened cell-cell adhesion involve altered protein turnover kinetics and defects in signalling pathways. Similar studies should improve our understanding of ARVC and provide a more accurate diagnostic algorithm.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Arrhythmogenic right ventricular cardiomyopathy, a disease of the desmosome; genetic and functional studies. |
| Identifier: | PQ ETD:525984 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1443947 |
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