Ankyrin-B: proteostasis and impact on cardiomyocyte behaviours in H9c2 cells

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dc.contributor.authorChen, Lena
dc.contributor.supervisorSwayne, Leigh Anne
dc.contributor.supervisorArbour, Laura
dc.date.accessioned2018-05-07T14:36:04Z
dc.date.copyright2018en_US
dc.date.issued2018-05-07
dc.degree.departmentProgram: Neuroscience
dc.degree.departmentDivision of Medical Sciences
dc.degree.departmentSchool of Medical Sciences
dc.degree.levelMaster of Science M.Sc.en_US
dc.description.abstractAnkyrin-B (Ank-B) is a crucial scaffolding protein regulating expression and localization of contractile machinery in the cardiac muscle. Recent genetic investigations in the First Nations Community, the Gitxsan of Northern BC, identified a mutation in Ank-B (p.S646F c.1937 C>T) associated with a cardiac arrhythmia, Long QT Syndrome Type 4 (LQTS4). Distinct from other LQTS4 subtypes, individuals harbouring the p.S646F variant exhibit development deficits including cardiomyopathies and accessory electrical pathways. How p.S646F interferes with the development of the heart is unknown due to a fundamental lack of understanding regarding Ank-B proteostasis and its role in cardiac differentiation. Initial in silico analyses predicted the p.S646F mutant to be deleterious to the Ank-B protein. Using in vitro techniques, I determined p.S646F mutant reduced levels of Ank-B in H9c2 rat ventricular cardiomyoblasts. Furthermore, haploinsufficiency in mice was previously shown to result in developmental cardiac deficits. I, therefore, hypothesized that p.S646F interferes with Ank-B proteostasis, thereby affecting cardiomyocyte development. I showed that p.S646F destabilized Ank-B in cardiomyoblasts, due to increased degradation via the proteasome. Furthermore, overexpression of p.S646F Ank-B had a significant impact on cellular behaviour including reduced cell viability, and altered expression of cellular differentiation markers. Together these data address critical knowledge gaps with regards to Ank-B protein homeostasis and the role of Ank-B in cardiomyocyte viability and development. These findings inform the diagnosis and treatment of patients with the p.S646F variant, creating potential targeted pathways of intervention, and furthering our understanding of the role of the Ank-B in the development of the heart.en_US
dc.description.embargo2019-04-26
dc.description.scholarlevelGraduateen_US
dc.identifier.bibliographicCitationSwayne LA, Murphy P, Asuri S, Chen L, Xu X, McIntosh S, Wang C, Lancione PJ, Roberts JD, Kerr C, Sanatai S, Sherwin E, Klin CF, Zhang M, Mohler P, Arbour LT. Novel variant in the ANK2 membrane-binding domain is associated with Ankyrin-B Syndrome and structural heart disease in a First Nations population with a high rate of LongQT Syndrome. Circulation: Cardiovascular Genetics.10(1) doi:10.1161/CIRCGENETICS.116.001537.en_US
dc.identifier.urihttp://hdl.handle.net/1828/9346
dc.languageEnglisheng
dc.language.isoenen_US
dc.rightsAvailable to the World Wide Weben_US
dc.subjectAnkyrin-Ben_US
dc.subjectProteostasisen_US
dc.subjectDevelopmenten_US
dc.subjectCardiomyocyteen_US
dc.subjectLong QTen_US
dc.titleAnkyrin-B: proteostasis and impact on cardiomyocyte behaviours in H9c2 cellsen_US
dc.typeThesisen_US

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