Intragenic Rescue of the Function of Long QT Syndrome-Causing Mutant hERG K+ Channels
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Authors
Davis, Jordan
Date
Type
thesis
Language
eng
Keyword
hERG , Mutations
Alternative Title
Abstract
The 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.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This 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.