The variant hERG/R148W associated with LQTS is a mutation that reduces current density on co-expression with the WT |
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Authors: | Asma Mechakra,Yohann Vincent,Philippe Chevalier,Gilles Millat,Eckhard Ficker,Marek Jastrzebski,Hugo Poulin,Valé rie Pouliot,Mohamed Chahine,Georges Christé |
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Affiliation: | 1. Laboratoire de Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France;2. Unité de Rythmologie, Centre National de Référence des Troubles du Rythme d''Origine Héréditaire, Hôpital Cardiovasculaire et Pneumologique L. Pradel, Hospices Civils de Lyon, Lyon F-69003, France;3. Laboratoire de Cardiogénétique, Centre de Biologie Est, Hospices Civils de Lyon, Lyon F-69003, France;4. MetroHealth Medical Center, Cleveland, OH, USA;5. Department of Cardiology and Hypertension, University Hospital, Kracow, Poland;6. Le Centre de Recherche en neuroscience, Institut Universitaire en Santé Mentale de Québec and Department of Medicine, Laval University, Québec, Canada |
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Abstract: | BackgroundA variant of the ether-à-go-go related channel (hERG), p.Arg148Trp (R148W) was found at heterozygous state in two infants who died from sudden infant death syndrome (SIDS), one with documented prolonged QTc and Torsade de Pointes (TdP), and in an adult woman with QTc > 500 ms, atrioventricular block and TdP. This variant was previously reported in cases of severe ventricular arrhythmia but very rarely in control subjects. Its classification as mutation or polymorphism awaited electrophysiological characterization.MethodsThe properties of this N-terminal, proximal domain, hERG variant were explored in Xenopus oocytes injected with the same amount of RNA encoding for either hERG/WT or hERG/R148W or their equimolar mixture. The human ventricular cell (TNNP) model was used to test the effects of changes in hERG current.ResultsR148W alone produced a current similar to the WT (369 ± 76 nA (mean ± SEM), n = 13 versus 342 ± 55 nA in WT, n = 13), while the co-expression of 1/2 WT + 1/2 R148W lowered the current by 29% versus WT (243 ± 35 nA, n = 13, p < 0.05). The voltage dependencies of steady-state activation and inactivation were not changed in the variant alone or in co-expression with the WT. The time constants of fast recovery from inactivation and of fast and slow deactivation analyzed between − 120 and + 20 mV were not changed. The voltage-dependent distribution of the current amplitudes among fast-, slow- and non-deactivating fractions was unaltered. A 6.6% increase in APD90 from 323.5 ms to 345 ms was observed using the human cardiac ventricular myocyte model.ConclusionsSuch a decrease in hERG current as evidenced here when co-expressing the hERG/R148W variant with the WT may have predisposed to the observed long QT syndrome and associated TdP. Therefore, the heterozygous carriers of hERG/R148W may be at risk of cardiac sudden death. |
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Keywords: | APD, Action potential duration APD90, APD at 90% repolarization DNA, Deoxyribonucleic acid cDNA, Cyclic DNA ECG, Electrocardiogram ESP, Exome Sequencing Project HEK293, Human-derived renal epithelial cell line number 293 hERG, Human ether-à -go-go related gene IKr, The rapid delayed rectifier current, underlied in cardiac cells by hERG LQTS, Long QT syndrome PAS domain, Per-Arnt-Sim domain in the N-terminal branch of the hERG protein QT, The QT interval of the ECG QTc, The corrected QT interval of the ECG, using Bazett's formula RNA, Ribonucleic acid mRNA, Messenger RNA RR, The RR interval of the ECG SCD, Sudden cardiac death SDS, Sodium dodecyl-sulfate SEM, Standard error of the mean SIDS, Sudden infant death syndrome SSCP, Single-strand conformational polymorphism TdP, Torsade de pointes TNNP, Ten Tusscher, Noble, Noble and Panfilov (2004), mathematical model of a human ventricular action potential WT, Wild-type |
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