Asma Mechakra1, Yohann Vincent1, Philippe Chevalier2, Gilles Millat3, Eckhard Ficker4, Marek Jastrzebski5, Hugo Poulin6, Valérie Pouliot6, Mohamed Chahine6, Georges Christé7. 1. Laboratoire de Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France. 2. Laboratoire de Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France; 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 Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France; 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. 7. Laboratoire de Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France. Electronic address: georges.christe@inserm.fr.
Abstract
BACKGROUND: A 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. METHODS: The 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. RESULTS: R148W 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. CONCLUSIONS: Such 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.
BACKGROUND: A 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. METHODS: The 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. RESULTS:R148W 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. CONCLUSIONS: Such 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.
Keywords:
APD; APD at 90% repolarization; APD90; Action potential duration; Arrhythmias; Channelopathy; Cyclic DNA; DNA; Deoxyribonucleic acid; ECG; ESP; Electrocardiogram; Exome Sequencing Project; HEK293; Human ether-à-go-go related channel; Human ether-à-go-go related gene; Human-derived renal epithelial cell line number 293; IKr; LQTS; Long QT syndrome; Messenger RNA; Mutation; PAS domain; Per-Arnt-Sim domain in the N-terminal branch of the hERG protein; QT; QTc; RNA; RR; Ribonucleic acid; SCD; SDS; SEM; SIDS; SSCP; Single-strand conformational polymorphism; Sodium dodecyl-sulfate; Standard error of the mean; Sudden cardiac death; Sudden death; Sudden infant death syndrome; TNNP; TdP; Ten Tusscher, Noble, Noble and Panfilov (2004), mathematical model of a human ventricular action potential; The QT interval of the ECG; The RR interval of the ECG; The corrected QT interval of the ECG, using Bazett's formula; The rapid delayed rectifier current, underlied in cardiac cells by hERG; Torsade de pointes; WT; Wild-type; cDNA; hERG; mRNA
Authors: Connie Jiang; Ebony Richardson; Jessica Farr; Adam P Hill; Rizwan Ullah; Brett M Kroncke; Steven M Harrison; Kate L Thomson; Jodie Ingles; Jamie I Vandenberg; Chai-Ann Ng Journal: Am J Hum Genet Date: 2022-06-09 Impact factor: 11.043
Authors: Krystian Kozek; Yuko Wada; Luca Sala; Isabelle Denjoy; Christian Egly; Matthew J O'Neill; Takeshi Aiba; Wataru Shimizu; Naomasa Makita; Taisuke Ishikawa; Lia Crotti; Carla Spazzolini; Maria-Christina Kotta; Federica Dagradi; Silvia Castelletti; Matteo Pedrazzini; Massimiliano Gnecchi; Antoine Leenhardt; Joe-Elie Salem; Seiko Ohno; Yi Zuo; Andrew M Glazer; Jonathan D Mosley; Dan M Roden; Bjorn C Knollmann; Jeffrey D Blume; Fabrice Extramiana; Peter J Schwartz; Minoru Horie; Brett M Kroncke Journal: Circ Genom Precis Med Date: 2021-07-26