Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias

Tomoyuki Kubota, Minoru Horie, Makoto Takano, Hidetada Yoshida, Kotoe Takenaka, Eiichi Watanabe, Takeshi Tsuchiya, Hideo Otani, Shigetake Sasayama

Research output: Contribution to journalArticle

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Abstract

Introduction: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. Methods and Results: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in ∼ 11% of the Japanese population. This 1727G > A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in ∼30% reduction in the slow delayed rectifier K + current I Ks without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I Ks dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.

Original languageEnglish
Pages (from-to)1223-1229
Number of pages7
JournalJournal of Cardiovascular Electrophysiology
Volume12
Issue number11
DOIs
Publication statusPublished - 01-01-2001

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KCNQ1 Potassium Channel
Long QT Syndrome
Single Nucleotide Polymorphism
Cardiac Arrhythmias
Genes
Phenotype
Precipitating Factors
Hypokalemia
Bradycardia
Ion Channels
Glycine
Serine
Population
Sequence Analysis
Exons
Polymerase Chain Reaction
Mutation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kubota, Tomoyuki ; Horie, Minoru ; Takano, Makoto ; Yoshida, Hidetada ; Takenaka, Kotoe ; Watanabe, Eiichi ; Tsuchiya, Takeshi ; Otani, Hideo ; Sasayama, Shigetake. / Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias. In: Journal of Cardiovascular Electrophysiology. 2001 ; Vol. 12, No. 11. pp. 1223-1229.
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abstract = "Introduction: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. Methods and Results: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in ∼ 11{\%} of the Japanese population. This 1727G > A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in ∼30{\%} reduction in the slow delayed rectifier K + current I Ks without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I Ks dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.",
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Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias. / Kubota, Tomoyuki; Horie, Minoru; Takano, Makoto; Yoshida, Hidetada; Takenaka, Kotoe; Watanabe, Eiichi; Tsuchiya, Takeshi; Otani, Hideo; Sasayama, Shigetake.

In: Journal of Cardiovascular Electrophysiology, Vol. 12, No. 11, 01.01.2001, p. 1223-1229.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias

AU - Kubota, Tomoyuki

AU - Horie, Minoru

AU - Takano, Makoto

AU - Yoshida, Hidetada

AU - Takenaka, Kotoe

AU - Watanabe, Eiichi

AU - Tsuchiya, Takeshi

AU - Otani, Hideo

AU - Sasayama, Shigetake

PY - 2001/1/1

Y1 - 2001/1/1

N2 - Introduction: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. Methods and Results: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in ∼ 11% of the Japanese population. This 1727G > A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in ∼30% reduction in the slow delayed rectifier K + current I Ks without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I Ks dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.

AB - Introduction: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. Methods and Results: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in ∼ 11% of the Japanese population. This 1727G > A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in ∼30% reduction in the slow delayed rectifier K + current I Ks without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. Conclusion: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I Ks dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.

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