title: Elevated heart rate triggers action potential alternans and sudden death. translational study of a homozygous KCNH2 mutation.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatric Cardiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweigmann
authors.affiliation: Division of Clinical Electrophysiology, Goethe University, Frankfurt, Germany; Div. of Cardiology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Biliczki
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Ramirez
authors.affiliation: Laboratory for Human Genetics, Martinsried, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Marschall
authors.affiliation: Institute of Cardiovascular Physiology, Goethe University, Frankfurt, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Takac
authors.affiliation: Institute of Cardiovascular Physiology, Goethe University, Frankfurt, Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: Section for Human Genetics, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kotzot
authors.affiliation: Division of Clinical Electrophysiology, Goethe University, Frankfurt, Germany.
authors.forename: Zenawit
authors.initials: Z
authors.lastname: Girmatsion
authors.affiliation: Division of Clinical Electrophysiology, Goethe University, Frankfurt, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Hohnloser
authors.affiliation: Division of Clinical Electrophysiology, Goethe University, Frankfurt, Germany; Div. of Cardiology, Deutsche Klinik für Diagnostik, Wiesbaden, Germany.
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Ehrlich
mesh_terms: D000200:Action Potentials / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005190:Family; D006339:Heart Rate / Q000235:genetics*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human