TY  - JOUR
A1  - Schweigmann, Ulrich
A1  - Biliczki, Peter
A1  - Ramirez, Rafael J.
A1  - Marschall, Christoph
A1  - Takac, Ina
A1  - Brandes, Ralf
A1  - Kotzot, Dieter
A1  - Girmatsion, Zenawit
A1  - Hohnloser, Stefan H.
A1  - Ehrlich, Joachim
T1  - Elevated heart rate triggers action potential alternans and sudden death : translational study of a homozygous KCNH2 mutation
T2  - PLoS One
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.
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/34490
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-344905
SN  - 1932-6203
N1  - Copyright: © 2014 Schweigmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
VL  - 9
IS  - (8):e103150
PB  - PLoS
CY  - Lawrence, Kan.
ER  -