Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes
Digital Object Identifier (DOI)
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.
Was this content written or created while at USF?
Citation / Publisher Attribution
Canadian Journal of Cardiology, v. 34, issue 9, p. 1174-1184
Scholar Commons Citation
Liu, Zhenning; Zheng, Renjian; Grushko, Michael J.; Uversky, Vladimir N.; and McDonald, Thomas V., "Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes" (2018). Molecular Medicine Faculty Publications. 248.