Use this URL to cite or link to this record in EThOS:
Title: Hypertrophic and dilated cardiomyopathies, the relationship of genotype to phenotype
Author: Jacques, Adam Matthew
ISNI:       0000 0004 2718 505X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
Most familial dilated and hypertrophic cardiomyopathies are caused by mutations in sarcomeric proteins. What remains to be answered is how mutations cause the cardiac phenotype and why mutations in the same protein can cause cardiomyopathies at different ends of the phenotypic spectrum. We collected human myocardium from HCM patients undergoing surgical myectomy, and familial and acquired DCM patients, undergoing cardiac transplantation. Patients were phenotyped before operation and blood taken for genotyping. We used the ProQ Diamond, Western Blot and in vitro motility assays to assess levels of phosphorylation, expression and function respectively of sarcomeric proteins. In HCM patients with myosin binding protein C mutations expression of MyBPC was reduced by 24% in myofilaments arguing strongly for happloinsufficiency as the disease causing mechanism. HCM myosin and MyBPC mutations, also affect cardiac contractility by dominant negative effects. Myosin mutation, Va1606Met, has direct and indirect effects on cardiac contraction. Filament sliding speed was greater and relaxation at pCa9 less complete than with other HCM myosins tested without mutations. The DCM troponin C mutation, Gly159Asp, acts as a poison polypeptide, changing thin filament regulation. Ca2+ -sensitivity of G159D troponin C was independent of the level of troponin phosphorylation. The uncoupling of the relationship between troponin phosphorylation and Ca2+-sensitivity, provides a novel mechanism for initiation of familial DCM. Post-translational modifications in sarcomeric proteins occur independently of genotype. Troponin I is dephosphorylated in DCM and HCM, leading to changes in Ca2+-sensitivity and cross-bridge turnover rate. Also both troponin and myosin from HCM tissue is functionally abnormal and MyBPC phosphorylation is reduced. In acquired heart failure dephosphorylation of Serines 23/24 on troponin I could account for the contractile defect in seen and MyBPC phosphorylation is also decreased. In summary we observed a hypocontractile molecular phenotype in HCM human heart tissue, similar to that seen in heart failure. These findings conflict with the observed clinical phenotype seen in HCM, which is often regarded as a hyperdynamic or hypercontractile state.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available