Trafficking-deficient long QT syndrome mutation KCNQ1-T587M confers severe clinical phenotype by impairment of KCNH2 membrane localization: Evidence for clinically significant IKr-IKs α-subunit interaction

P. Biliczki, Zenawit Girmatsion, Ralf P. Brandes, Sabine Harenkamp, Bruno Pitard, Flavien Charpentier, Terence E. Hébert, Stefan H. Hohnloser, Isabelle Baró, Stanley Nattel, Joachim R. Ehrlich

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: KCNQ1-T587M is a trafficking-deficient long QT syndrome (LQTS) missense mutation. Affected patients exhibit severe clinical phenotypes that are not explained by the mutant's effects on IKs. Previous work showed a KCNH2 and KCNQ1 α-subunit interaction that increases KCNH2 membrane localization and function. Objective: We hypothesized that failure of trafficking-deficient KCNQ1-T587M to enhance KCNH2 membrane expression could reduce KCNH2 current versus wild-type KCNQ1 (KCNQ1-WT), contributing to the LQTS phenotype of KCNQ1-T587M carriers. Methods: Patch-clamp, protein biochemical studies, confocal imaging, and in vivo transfection of guinea pig cardiomyocytes were performed. Results: KCNQ1-T587M failed to generate functional current when coexpressed with KCNE1 and caused haploinsufficiency when coexpressed with KCNQ1-WT/KCNE1. Coexpression of KCNQ1-WT with KCNH2 increased IKCNH2 versus KCNH2 alone (P KCNH2 upon coexpression substantially compared with coexpression with KCNQ1-WT (P Kr in isolated cardiomyocytes. Conclusion: The trafficking-deficient LQTS mutation KCNQ1-T587M fails to show the chaperoning function that enhances KCNH2 membrane localization with KCNQ1-WT. This novel mechanism results in reduced IKCNH2, which would be expected to decrease repolarization reserve and synergize with reduced IKCNQ1 caused directly by the mutation, potentially explaining the malignant clinical phenotype in affected patients.

Original languageEnglish
Pages (from-to)1792-1801
Number of pages10
JournalHeart Rhythm
Volume6
Issue number12
DOIs
Publication statusPublished - Dec 2009

Fingerprint

Long QT Syndrome
Phenotype
Cardiac Myocytes
Mutation
Membranes
Haploinsufficiency
Missense Mutation
Transfection
Guinea Pigs
Proteins

Keywords

  • KCNH2
  • KCNQ1
  • Long QT syndrome
  • Sudden cardiac death
  • Torsades de pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Trafficking-deficient long QT syndrome mutation KCNQ1-T587M confers severe clinical phenotype by impairment of KCNH2 membrane localization : Evidence for clinically significant IKr-IKs α-subunit interaction. / Biliczki, P.; Girmatsion, Zenawit; Brandes, Ralf P.; Harenkamp, Sabine; Pitard, Bruno; Charpentier, Flavien; Hébert, Terence E.; Hohnloser, Stefan H.; Baró, Isabelle; Nattel, Stanley; Ehrlich, Joachim R.

In: Heart Rhythm, Vol. 6, No. 12, 12.2009, p. 1792-1801.

Research output: Contribution to journalArticle

Biliczki, P. ; Girmatsion, Zenawit ; Brandes, Ralf P. ; Harenkamp, Sabine ; Pitard, Bruno ; Charpentier, Flavien ; Hébert, Terence E. ; Hohnloser, Stefan H. ; Baró, Isabelle ; Nattel, Stanley ; Ehrlich, Joachim R. / Trafficking-deficient long QT syndrome mutation KCNQ1-T587M confers severe clinical phenotype by impairment of KCNH2 membrane localization : Evidence for clinically significant IKr-IKs α-subunit interaction. In: Heart Rhythm. 2009 ; Vol. 6, No. 12. pp. 1792-1801.
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abstract = "Background: KCNQ1-T587M is a trafficking-deficient long QT syndrome (LQTS) missense mutation. Affected patients exhibit severe clinical phenotypes that are not explained by the mutant's effects on IKs. Previous work showed a KCNH2 and KCNQ1 α-subunit interaction that increases KCNH2 membrane localization and function. Objective: We hypothesized that failure of trafficking-deficient KCNQ1-T587M to enhance KCNH2 membrane expression could reduce KCNH2 current versus wild-type KCNQ1 (KCNQ1-WT), contributing to the LQTS phenotype of KCNQ1-T587M carriers. Methods: Patch-clamp, protein biochemical studies, confocal imaging, and in vivo transfection of guinea pig cardiomyocytes were performed. Results: KCNQ1-T587M failed to generate functional current when coexpressed with KCNE1 and caused haploinsufficiency when coexpressed with KCNQ1-WT/KCNE1. Coexpression of KCNQ1-WT with KCNH2 increased IKCNH2 versus KCNH2 alone (P KCNH2 upon coexpression substantially compared with coexpression with KCNQ1-WT (P Kr in isolated cardiomyocytes. Conclusion: The trafficking-deficient LQTS mutation KCNQ1-T587M fails to show the chaperoning function that enhances KCNH2 membrane localization with KCNQ1-WT. This novel mechanism results in reduced IKCNH2, which would be expected to decrease repolarization reserve and synergize with reduced IKCNQ1 caused directly by the mutation, potentially explaining the malignant clinical phenotype in affected patients.",
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T1 - Trafficking-deficient long QT syndrome mutation KCNQ1-T587M confers severe clinical phenotype by impairment of KCNH2 membrane localization

T2 - Evidence for clinically significant IKr-IKs α-subunit interaction

AU - Biliczki, P.

AU - Girmatsion, Zenawit

AU - Brandes, Ralf P.

AU - Harenkamp, Sabine

AU - Pitard, Bruno

AU - Charpentier, Flavien

AU - Hébert, Terence E.

AU - Hohnloser, Stefan H.

AU - Baró, Isabelle

AU - Nattel, Stanley

AU - Ehrlich, Joachim R.

PY - 2009/12

Y1 - 2009/12

N2 - Background: KCNQ1-T587M is a trafficking-deficient long QT syndrome (LQTS) missense mutation. Affected patients exhibit severe clinical phenotypes that are not explained by the mutant's effects on IKs. Previous work showed a KCNH2 and KCNQ1 α-subunit interaction that increases KCNH2 membrane localization and function. Objective: We hypothesized that failure of trafficking-deficient KCNQ1-T587M to enhance KCNH2 membrane expression could reduce KCNH2 current versus wild-type KCNQ1 (KCNQ1-WT), contributing to the LQTS phenotype of KCNQ1-T587M carriers. Methods: Patch-clamp, protein biochemical studies, confocal imaging, and in vivo transfection of guinea pig cardiomyocytes were performed. Results: KCNQ1-T587M failed to generate functional current when coexpressed with KCNE1 and caused haploinsufficiency when coexpressed with KCNQ1-WT/KCNE1. Coexpression of KCNQ1-WT with KCNH2 increased IKCNH2 versus KCNH2 alone (P KCNH2 upon coexpression substantially compared with coexpression with KCNQ1-WT (P Kr in isolated cardiomyocytes. Conclusion: The trafficking-deficient LQTS mutation KCNQ1-T587M fails to show the chaperoning function that enhances KCNH2 membrane localization with KCNQ1-WT. This novel mechanism results in reduced IKCNH2, which would be expected to decrease repolarization reserve and synergize with reduced IKCNQ1 caused directly by the mutation, potentially explaining the malignant clinical phenotype in affected patients.

AB - Background: KCNQ1-T587M is a trafficking-deficient long QT syndrome (LQTS) missense mutation. Affected patients exhibit severe clinical phenotypes that are not explained by the mutant's effects on IKs. Previous work showed a KCNH2 and KCNQ1 α-subunit interaction that increases KCNH2 membrane localization and function. Objective: We hypothesized that failure of trafficking-deficient KCNQ1-T587M to enhance KCNH2 membrane expression could reduce KCNH2 current versus wild-type KCNQ1 (KCNQ1-WT), contributing to the LQTS phenotype of KCNQ1-T587M carriers. Methods: Patch-clamp, protein biochemical studies, confocal imaging, and in vivo transfection of guinea pig cardiomyocytes were performed. Results: KCNQ1-T587M failed to generate functional current when coexpressed with KCNE1 and caused haploinsufficiency when coexpressed with KCNQ1-WT/KCNE1. Coexpression of KCNQ1-WT with KCNH2 increased IKCNH2 versus KCNH2 alone (P KCNH2 upon coexpression substantially compared with coexpression with KCNQ1-WT (P Kr in isolated cardiomyocytes. Conclusion: The trafficking-deficient LQTS mutation KCNQ1-T587M fails to show the chaperoning function that enhances KCNH2 membrane localization with KCNQ1-WT. This novel mechanism results in reduced IKCNH2, which would be expected to decrease repolarization reserve and synergize with reduced IKCNQ1 caused directly by the mutation, potentially explaining the malignant clinical phenotype in affected patients.

KW - KCNH2

KW - KCNQ1

KW - Long QT syndrome

KW - Sudden cardiac death

KW - Torsades de pointes

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