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Effects of cardiomyopathy-related mutations in alpha-cardiac actin on the actin-myosin complex

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dc.contributor.author Dahari
dc.date.accessioned 2012-09-13T13:46:39Z
dc.date.available 2012-09-13T13:46:39Z
dc.date.copyright 2012-09
dc.date.created 2012-08-27
dc.date.issued 2012-09-13
dc.identifier.uri http://hdl.handle.net/10214/3980
dc.description.abstract Cardiomyopathies are a distinct class of heart disease and are the third most common cause of heart failure. These conditions are generally characterized by remodeling of the left ventricle; however, the molecular mechanisms leading to the pathological states are still not fully understood. Mutated genes encoding for sarcomeric proteins have been shown to influence the development of cardiomyopathies. Missense mutations in alpha-cardiac actin (ACTC) have been associated with both hypertrophic and dilated cardiomyopathies (HCM and DCM respectively). Twelve of these mutations contribute to the onset of HCM: E99K, P164A, A331P, Y166C, A230V, A295S, M305L, S271F, H88Y, R95C, F90del and R312C while two contribute to the onset of DCM: E361G and R312H. These mutations are proposed to have detrimental effects on the structure and function of alpha-cardiac actin, thus leading to the diseased state. A295S ACTC did not exhibit intrinsic defects in protein folding and polymerization as seen with other ACTC variants with subdomain 3 mutations. Actin-activated ATPase rates measured showed the E99K ACTC variant increased the ATPase rate of skeletal myosin by approximately 30% compared to WT ACTC. E99K ACTC also exhibited decreased filament motility approximately 40-50% slower that WT ACTC at all ionic and ATP conditions examined demonstrating a reduction in force generation. These results demonstrate deficiencies in myosin binding of the E99K ACTC variant, providing insight into the primary molecular disruptions leading to the development of cardiomyopathies. en_US
dc.description.sponsorship Heart and Stroke Foundation en_US
dc.language.iso en en_US
dc.subject cardiomyopathy en_US
dc.title Effects of cardiomyopathy-related mutations in alpha-cardiac actin on the actin-myosin complex en_US
dc.type Thesis en_US
dc.degree.programme Molecular and Cellular Biology en_US
dc.degree.name Master of Science en_US
dc.degree.department Department of Molecular and Cellular Biology en_US
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