Elevated heart rate triggers action potential alternans and sudden death. Translational study of a homozygous KCNH2 mutation

Ulrich Schweigmann, P. Biliczki, Rafael J. Ramirez, Christoph Marschall, Ina Takac, Ralf P. Brandes, Dieter Kotzot, Zenawit Girmatsion, Stefan H. Hohnloser, Joachim R. Ehrlich

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Methods and Results: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ∼506 ms with notched T waves). Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Conclusion: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.

Original languageEnglish
Article numbere103150
JournalPLoS One
Volume9
Issue number8
DOIs
Publication statusPublished - Aug 20 2014

Fingerprint

Biochemistry
Confocal microscopy
action potentials
Sudden Death
Action Potentials
heart rate
Long QT Syndrome
Heart Rate
death
mutation
Mutagenesis
Mutation
Clamping devices
Cell culture
duration
Sudden Cardiac Death
Precipitates
Proteins
Confocal Microscopy
Computer Simulation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Elevated heart rate triggers action potential alternans and sudden death. Translational study of a homozygous KCNH2 mutation. / Schweigmann, Ulrich; Biliczki, P.; Ramirez, Rafael J.; Marschall, Christoph; Takac, Ina; Brandes, Ralf P.; Kotzot, Dieter; Girmatsion, Zenawit; Hohnloser, Stefan H.; Ehrlich, Joachim R.

In: PLoS One, Vol. 9, No. 8, e103150, 20.08.2014.

Research output: Contribution to journalArticle

Schweigmann, U, Biliczki, P, Ramirez, RJ, Marschall, C, Takac, I, Brandes, RP, Kotzot, D, Girmatsion, Z, Hohnloser, SH & Ehrlich, JR 2014, 'Elevated heart rate triggers action potential alternans and sudden death. Translational study of a homozygous KCNH2 mutation', PLoS One, vol. 9, no. 8, e103150. https://doi.org/10.1371/journal.pone.0103150
Schweigmann, Ulrich ; Biliczki, P. ; Ramirez, Rafael J. ; Marschall, Christoph ; Takac, Ina ; Brandes, Ralf P. ; Kotzot, Dieter ; Girmatsion, Zenawit ; Hohnloser, Stefan H. ; Ehrlich, Joachim R. / Elevated heart rate triggers action potential alternans and sudden death. Translational study of a homozygous KCNH2 mutation. In: PLoS One. 2014 ; Vol. 9, No. 8.
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author = "Ulrich Schweigmann and P. Biliczki and Ramirez, {Rafael J.} and Christoph Marschall and Ina Takac and Brandes, {Ralf P.} and Dieter Kotzot and Zenawit Girmatsion and Hohnloser, {Stefan H.} and Ehrlich, {Joachim R.}",
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AU - Schweigmann, Ulrich

AU - Biliczki, P.

AU - Ramirez, Rafael J.

AU - Marschall, Christoph

AU - Takac, Ina

AU - Brandes, Ralf P.

AU - Kotzot, Dieter

AU - Girmatsion, Zenawit

AU - Hohnloser, Stefan H.

AU - Ehrlich, Joachim R.

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N2 - Background: Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Methods and Results: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ∼506 ms with notched T waves). Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Conclusion: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.

AB - Background: Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Methods and Results: Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ∼506 ms with notched T waves). Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Conclusion: Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.

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