Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes

Zhenning Liu, Renjian Zheng, Michael J. Grushko, Vladimir N. Uversky, Thomas V. McDonald

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Abstract

Background: Deleterious mutations in KCNQ1 may lead to an autosomal dominant form of long QT syndrome (LQTS) (Romano-Ward) or autosomal recessive form (Jervell and Lange-Nielsen). Both are associated with severe ventricular tachyarrhythmias due to the reduction of the slowly activating delayed rectifier K+ current (IKs). Our objective was to investigate the functional consequences of KCNQ1-R562S mutation in an atypical form of KCNQ1-linked LQTS. Methods: Mutant KCNQ1-R562S was analyzed via confocal imaging, surface biotinylation assays, co-immunoprecipitation, phosphatidylinositol-4,5-bisphosphate pulldown test, whole-cell patch clamp, and computational intrinsic disorder analyses. Results: Protein expression, assembly with KCNE1, and trafficking to the surface membrane of KCNQ1-R562S were comparable with wild-type channels. The most significant functional effect of the R562S mutation was a depolarizing shift in the voltage dependence of activation that was dependent on association with KCNE1. The biophysical abnormality was only partially dominant over coexpressed wild-type channels. R562S mutation impaired C-terminal association with membrane phosphatidylinositol-4,5-bisphosphate. These changes led to compromised rate-related accumulation of repolarizing current that is an important property of normal IKs. Conclusions: KCNQ1-R562S mutation reduces effective IKs due to channel gating alteration with a mild clinical expression in the heterozygous state due to minimal dominant phenotype. In the homozygous state, it is exhibited with a moderately severe LQTS phenotype due to the incomplete absence of IKs.

Original languageEnglish (US)
Pages (from-to)1174-1184
Number of pages11
JournalCanadian Journal of Cardiology
Volume34
Issue number9
DOIs
Publication statusPublished - Sep 2018

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ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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