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dc.contributor.authorDavis, Jordanen
dc.date.accessioned2018-08-28T19:48:12Z
dc.date.available2018-08-28T19:48:12Z
dc.identifier.urihttp://hdl.handle.net/1974/24476
dc.description.abstractThe human-ether-a-go-go-related gene (hERG) encodes the pore forming subunit of the rapidly activating delayed rectifier K+ channel (IKr), which is important for the repolarization phase of ventricular cardiac action potentials. A reduction in IKr due to a loss of hERG function can lead to long QT syndrome (LQTS). As such, there are a variety of hERG mutations known to cause LQTS. The majority of these mutations are thought to be trafficking deficient, including the G601S mutation. It has been shown that the plasma membrane (PM) expression of the G601S hERG mutant can be rescued by reduced-temperature culture. Additionally, it has been shown that hERG channels undergo rapid internalization in 0 mM K+o culture conditions, but this can also be prevented by reduced-temperature culture. Thus, the hypothesis of this thesis is that certain hERG mutants, including G601S, can traffic to the plasma membrane where they internalize due to impaired stability, similar to WT hERG channels in 0 mM K+ conditions. To test this hypothesis, a secondary mutation, S624T, which does not require K+o for stable PM expression, was added to the G601S mutant hERG channel. The addition of S624T intragenically suppressed the loss-of-function G601S phenotype and significantly rescued G601S expression and current. The addition of S624T also rescued LQTS-causing hERG mutants T474I and P596R. These data reveals the most effective intragenic rescue of LQTS-causing hERG mutants to date and lends insight into the mechanisms underlying the loss-of-function phenotype of certain LQTS-causing hERG mutants.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjecthERGen
dc.subjectMutationsen
dc.titleIntragenic Rescue of the Function of Long QT Syndrome-Causing Mutant hERG K+ Channelsen
dc.typethesisen
dc.description.degreeM.Sc.en
dc.contributor.supervisorZhang, Shetuanen
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.degree.grantorQueen's University at Kingstonen


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