Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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)
JournalCanadian Journal of Cardiology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Long QT Syndrome
Phenotype
Mutation
Phosphatidylinositols
Biotinylation
Membranes
Immunoprecipitation
Tachycardia
Proteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes. / Liu, Zhenning; Zheng, Renjian; Grushko, Michael J.; Uversky, Vladimir N.; McDonald, Thomas V.

In: Canadian Journal of Cardiology, 01.01.2018.

Research output: Contribution to journalArticle

@article{20c349c3649940b5ab454de03059cf81,
title = "Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes",
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.",
author = "Zhenning Liu and Renjian Zheng and Grushko, {Michael J.} and Uversky, {Vladimir N.} and McDonald, {Thomas V.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.cjca.2018.06.015",
language = "English (US)",
journal = "Canadian Journal of Cardiology",
issn = "0828-282X",
publisher = "Pulsus Group Inc.",

}

TY - JOUR

T1 - Functionally Aberrant Mutant KCNQ1 With Intermediate Heterozygous and Homozygous Phenotypes

AU - Liu, Zhenning

AU - Zheng, Renjian

AU - Grushko, Michael J.

AU - Uversky, Vladimir N.

AU - McDonald, Thomas V.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85051058384&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051058384&partnerID=8YFLogxK

U2 - 10.1016/j.cjca.2018.06.015

DO - 10.1016/j.cjca.2018.06.015

M3 - Article

JO - Canadian Journal of Cardiology

JF - Canadian Journal of Cardiology

SN - 0828-282X

ER -