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Title: Molecular mechanisms of myopathies
Author: Memo, Massimiliano
ISNI:       0000 0004 2728 7216
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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This study was aimed at the investigation of the mechanisms by which mutations on proteins of the thin filaments could lead to cardiac and skeletal muscle diseases. The contractile properties of reconstituted thin filaments were assessed using the quantitative in vitro motility assay. The cardiac disease investigated was the dilated cardiomyopathy (DCM). Pilot work on 2 mutants indicated that, contrarily to what was believed in the past, the molecular phenotype generated by mutations on thin filament proteins linked to the disease was not a reduced absolute Ca2+-sensitivity and cross-bridge turnover rate, but an uncoupling between the phosphorylation level of troponin I and the Ca2+-sensitivity. In this thesis I will present the confirmation of the hypothesis with 7 DCM causing mutations. At least one mutation on each of the thin filaments subunits was tested and they all shared that molecular phenotype despite differences in the absolute Ca2+- sensitivity. Mutations on β- and γ-tropomyosin linked to 3 skeletal muscle diseases, Nemaline myopathy, Cap disease and congenital fibre type disproportion (CFTD), were taken into consideration. Some of these mutations were also reported to cause more than one of these diseases. The β-tropomyosin mutations indicated that there is not a clear correlation between molecular phenotype and disease, as different modifications of the contractile properties seem to lead to the same disease. One of the β-tropomyosin mutations (ΔK7), though, as another mutation on skeletal actin (K326N) that was investigated, showed a new hypercontractile phenotype connected to a gain-offunction molecular phenotype, which led to a change in the clinical diagnosis. The experiments performed with the γ-tropomyosin mutants encountered many technical issues but indicated that a common phenotype of decreased Ca2+-sensitivity might be connected to CFTD, observation supported also by a β-tropomyosin mutant connected only to that disease.
Supervisor: Marston, Steve ; Messer, Andrew Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral