Partially dominant mutant channel defect corresponding with intermediate LQT2 phenotype

Yamini Krishnan, Renjian Zheng, Christine Walsh, Yingying Tang, Thomas V. McDonald

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: The hereditary Long QT Syndrome is a common cardiac disorder where ventricular repolarization is delayed, abnormally prolonging the QTc interval on electrocardiograms. LQTS is linked to various genetic loci, including the KCNH2 (HERG) gene that encodes the α-subunit of the cardiac potassium channel that carries I Kr. Here, we report and characterize a novel pathologic missense mutation, G816V HERG, in a patient with sudden cardiac death. Methods: Autopsy-derived tissue sample was used for DNA extraction and sequencing from an unexpected sudden death victim. The G816V HERG mutation was studied using heterologous expression in mammalian cell culture, whole cell patch clamp, confocal immunofluorescence, and immunochemical analyses. Results: The mutant G816V HERG channel has reduced protein expression and shows a trafficking defective phenotype that is incapable of carrying current when expressed at physiological temperatures. The mutant channel showed reduced cell surface localization compared to wild-type HERG (WT HERG) but the mutant and wild-type subunits are capable of interacting. Expression studies at reduced temperatures enabled partial rescue of the trafficking defect with appearance of potassium currents, albeit with reduced current density and altered voltage-dependent activation. Lastly, we examined a potential role for hypokalemia as a contributory factor to the patient's lethal arrhythmia by possible low-potassium-induced degradation of WT HERG and haplo-insufficiency of G816V HERG. Conclusion: The G816V mutation in HERG causes a trafficking defect that acts in a partially dominant negative manner. This intermediate severity defect agrees with the mild clinical presentation in other family members harboring the same mutation. Possible hypokalemia in the proband induced WT HERG degradation combined with haplo-insufficiency may have further compromised repolarization reserve and contributed to the lethal arrhythmia.

Original languageEnglish (US)
Pages (from-to)3-16
Number of pages14
JournalPACE - Pacing and Clinical Electrophysiology
Volume35
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Hypokalemia
Phenotype
Mutation
Cardiac Arrhythmias
Potassium
Long QT Syndrome
Temperature
Genetic Loci
Potassium Channels
Sudden Cardiac Death
Missense Mutation
Sudden Death
DNA Sequence Analysis
Fluorescent Antibody Technique
Autopsy
Electrocardiography
Cell Culture Techniques
Genes
Proteins

Keywords

  • G816V
  • HERG
  • hypokalemia
  • I
  • KCHN2
  • LQT2
  • sudden death
  • ventricular arrhythmia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Partially dominant mutant channel defect corresponding with intermediate LQT2 phenotype. / Krishnan, Yamini; Zheng, Renjian; Walsh, Christine; Tang, Yingying; McDonald, Thomas V.

In: PACE - Pacing and Clinical Electrophysiology, Vol. 35, No. 1, 01.2012, p. 3-16.

Research output: Contribution to journalArticle

Krishnan, Yamini ; Zheng, Renjian ; Walsh, Christine ; Tang, Yingying ; McDonald, Thomas V. / Partially dominant mutant channel defect corresponding with intermediate LQT2 phenotype. In: PACE - Pacing and Clinical Electrophysiology. 2012 ; Vol. 35, No. 1. pp. 3-16.
@article{4b39f3c915a9405ca5100b4ba0f1be87,
title = "Partially dominant mutant channel defect corresponding with intermediate LQT2 phenotype",
abstract = "Background: The hereditary Long QT Syndrome is a common cardiac disorder where ventricular repolarization is delayed, abnormally prolonging the QTc interval on electrocardiograms. LQTS is linked to various genetic loci, including the KCNH2 (HERG) gene that encodes the α-subunit of the cardiac potassium channel that carries I Kr. Here, we report and characterize a novel pathologic missense mutation, G816V HERG, in a patient with sudden cardiac death. Methods: Autopsy-derived tissue sample was used for DNA extraction and sequencing from an unexpected sudden death victim. The G816V HERG mutation was studied using heterologous expression in mammalian cell culture, whole cell patch clamp, confocal immunofluorescence, and immunochemical analyses. Results: The mutant G816V HERG channel has reduced protein expression and shows a trafficking defective phenotype that is incapable of carrying current when expressed at physiological temperatures. The mutant channel showed reduced cell surface localization compared to wild-type HERG (WT HERG) but the mutant and wild-type subunits are capable of interacting. Expression studies at reduced temperatures enabled partial rescue of the trafficking defect with appearance of potassium currents, albeit with reduced current density and altered voltage-dependent activation. Lastly, we examined a potential role for hypokalemia as a contributory factor to the patient's lethal arrhythmia by possible low-potassium-induced degradation of WT HERG and haplo-insufficiency of G816V HERG. Conclusion: The G816V mutation in HERG causes a trafficking defect that acts in a partially dominant negative manner. This intermediate severity defect agrees with the mild clinical presentation in other family members harboring the same mutation. Possible hypokalemia in the proband induced WT HERG degradation combined with haplo-insufficiency may have further compromised repolarization reserve and contributed to the lethal arrhythmia.",
keywords = "G816V, HERG, hypokalemia, I, KCHN2, LQT2, sudden death, ventricular arrhythmia",
author = "Yamini Krishnan and Renjian Zheng and Christine Walsh and Yingying Tang and McDonald, {Thomas V.}",
year = "2012",
month = "1",
doi = "10.1111/j.1540-8159.2011.03222.x",
language = "English (US)",
volume = "35",
pages = "3--16",
journal = "PACE - Pacing and Clinical Electrophysiology",
issn = "0147-8389",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Partially dominant mutant channel defect corresponding with intermediate LQT2 phenotype

AU - Krishnan, Yamini

AU - Zheng, Renjian

AU - Walsh, Christine

AU - Tang, Yingying

AU - McDonald, Thomas V.

PY - 2012/1

Y1 - 2012/1

N2 - Background: The hereditary Long QT Syndrome is a common cardiac disorder where ventricular repolarization is delayed, abnormally prolonging the QTc interval on electrocardiograms. LQTS is linked to various genetic loci, including the KCNH2 (HERG) gene that encodes the α-subunit of the cardiac potassium channel that carries I Kr. Here, we report and characterize a novel pathologic missense mutation, G816V HERG, in a patient with sudden cardiac death. Methods: Autopsy-derived tissue sample was used for DNA extraction and sequencing from an unexpected sudden death victim. The G816V HERG mutation was studied using heterologous expression in mammalian cell culture, whole cell patch clamp, confocal immunofluorescence, and immunochemical analyses. Results: The mutant G816V HERG channel has reduced protein expression and shows a trafficking defective phenotype that is incapable of carrying current when expressed at physiological temperatures. The mutant channel showed reduced cell surface localization compared to wild-type HERG (WT HERG) but the mutant and wild-type subunits are capable of interacting. Expression studies at reduced temperatures enabled partial rescue of the trafficking defect with appearance of potassium currents, albeit with reduced current density and altered voltage-dependent activation. Lastly, we examined a potential role for hypokalemia as a contributory factor to the patient's lethal arrhythmia by possible low-potassium-induced degradation of WT HERG and haplo-insufficiency of G816V HERG. Conclusion: The G816V mutation in HERG causes a trafficking defect that acts in a partially dominant negative manner. This intermediate severity defect agrees with the mild clinical presentation in other family members harboring the same mutation. Possible hypokalemia in the proband induced WT HERG degradation combined with haplo-insufficiency may have further compromised repolarization reserve and contributed to the lethal arrhythmia.

AB - Background: The hereditary Long QT Syndrome is a common cardiac disorder where ventricular repolarization is delayed, abnormally prolonging the QTc interval on electrocardiograms. LQTS is linked to various genetic loci, including the KCNH2 (HERG) gene that encodes the α-subunit of the cardiac potassium channel that carries I Kr. Here, we report and characterize a novel pathologic missense mutation, G816V HERG, in a patient with sudden cardiac death. Methods: Autopsy-derived tissue sample was used for DNA extraction and sequencing from an unexpected sudden death victim. The G816V HERG mutation was studied using heterologous expression in mammalian cell culture, whole cell patch clamp, confocal immunofluorescence, and immunochemical analyses. Results: The mutant G816V HERG channel has reduced protein expression and shows a trafficking defective phenotype that is incapable of carrying current when expressed at physiological temperatures. The mutant channel showed reduced cell surface localization compared to wild-type HERG (WT HERG) but the mutant and wild-type subunits are capable of interacting. Expression studies at reduced temperatures enabled partial rescue of the trafficking defect with appearance of potassium currents, albeit with reduced current density and altered voltage-dependent activation. Lastly, we examined a potential role for hypokalemia as a contributory factor to the patient's lethal arrhythmia by possible low-potassium-induced degradation of WT HERG and haplo-insufficiency of G816V HERG. Conclusion: The G816V mutation in HERG causes a trafficking defect that acts in a partially dominant negative manner. This intermediate severity defect agrees with the mild clinical presentation in other family members harboring the same mutation. Possible hypokalemia in the proband induced WT HERG degradation combined with haplo-insufficiency may have further compromised repolarization reserve and contributed to the lethal arrhythmia.

KW - G816V

KW - HERG

KW - hypokalemia

KW - I

KW - KCHN2

KW - LQT2

KW - sudden death

KW - ventricular arrhythmia

UR - http://www.scopus.com/inward/record.url?scp=84855897480&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855897480&partnerID=8YFLogxK

U2 - 10.1111/j.1540-8159.2011.03222.x

DO - 10.1111/j.1540-8159.2011.03222.x

M3 - Article

VL - 35

SP - 3

EP - 16

JO - PACE - Pacing and Clinical Electrophysiology

JF - PACE - Pacing and Clinical Electrophysiology

SN - 0147-8389

IS - 1

ER -