Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations

Matthew D. Perry*, Chai Ann Ng, Kevin Phan, Erikka David, Kieran Steer, Mark J. Hunter, Stefan A. Mann, Mohammad Imtiaz, Adam P. Hill, Ying Ke, Jamie I. Vandenberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


In the heart, Kv11.1 channels pass the rapid delayed rectifier current (IKr) which plays critical roles in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Over 500 inherited mutations in Kv11.1 are known to cause long QT syndrome type 2 (LQTS2), a cardiac electrical disorder associated with an increased risk of life threatening arrhythmias. Most missense mutations in Kv11.1 reduce the amount of channel protein expressed at the membrane and, as a consequence, there has been considerable interest in developing pharmacological agents to rescue the expression of these channels. However, pharmacological chaperones will only have clinical utility if the mutant Kv11.1 channels function normally after membrane expression is restored. The aim of this study was to characterize the gating phenotype for a subset of LQTS2 mutations to assess what proportion of mutations may be suitable for rescue. As an initial screen we used reduced temperature to rescue expression defects of mutant channels expressed in Xenopus laevis oocytes. Over half (∼56%) of Kv11.1 mutants exhibited functional gating defects that either dramatically reduced the amount of current contributing to cardiac action potential repolarization and/or reduced the amount of protective current elicited in response to premature depolarizations. Our data demonstrate that if pharmacological rescue of protein expression defects is going to have clinical utility in the treatment of LQTS2 then it will be important to assess the gating phenotype of LQTS2 mutations before attempting rescue.

Original languageEnglish
Pages (from-to)4031-4049
Number of pages19
JournalJournal of Physiology
Issue number14
Publication statusPublished - 15 Jul 2016
Externally publishedYes


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