Use this URL to cite or link to this record in EThOS:
Title: Arrhythmogenic right ventricular cardiomyopathy, a disease of the desmosome : genetic and functional studies
Author: Asimaki, Angeliki
ISNI:       0000 0004 2668 2142
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2008
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available