The variant hERG/R148W associated with LQTS is a mutation that reduces current density on co-expression with the WT

• Published in: Gene Vol. 536; no. 2; pp. 348 - 356
• Main Authors: Mechakra, Asma, Vincent, Yohann, Chevalier, Philippe, Millat, Gilles, Ficker, Eckhard, Jastrzebski, Marek, Poulin, Hugo, Pouliot, Valérie, Chahine, Mohamed, Christé, Georges
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.02.2014; Elsevier
• Subjects: Adult; adults; Animals; arrhythmia; Arrhythmias; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Brugada Syndrome; Cardiac Conduction System Disease; Cell Line; Channelopathy; death; Death, Sudden, Cardiac; electrophysiology; Female; Heart - physiopathology; Heart Conduction System - abnormalities; Heart Conduction System - metabolism; HEK293 Cells; heterozygosity; Heterozygote; Human ether-à-go-go related channel; Humans; Infant; infants; Life Sciences; Long QT syndrome; Long QT Syndrome - genetics; Long QT Syndrome - metabolism; Male; Mutation; Mutation - genetics; Myocytes, Cardiac - metabolism; Oocysts - metabolism; oocytes; risk; RNA; Sudden death; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptional Regulator ERG; women; Xenopus; Xenopus - genetics; Xenopus - metabolism; RR; TdP; SIDS; RNA; Channelopathy; mRNA; IKr; HEK293; Long QT syndrome; cDNA; TNNP; WT; QTc; hERG; ESP; QT; SDS; Sudden death; LQTS; ECG; SSCP; Human ether-à-go-go related channel; PAS domain; APD; APD90; SCD; DNA; SEM; Mutation; Arrhythmias; The QT interval of the ECG; The rapid delayed rectifier current, underlied in cardiac cells by hERG; Per-Arnt-Sim domain in the N-terminal branch of the hERG protein; Single-strand conformational polymorphism; Messenger RNA; Sudden infant death syndrome; Action potential duration; Torsade de pointes; Human ether-à-go-go related gene; Standard error of the mean; Wild-type; Electrocardiogram; Ten Tusscher, Noble, Noble and Panfilov , mathematical model of a human ventricular action potential; Cyclic DNA; The RR interval of the ECG; Deoxyribonucleic acid; Ribonucleic acid; Human-derived renal epithelial cell line number 293; Sudden cardiac death; APD at 90% repolarization; The corrected QT interval of the ECG, using Bazett's formula; Sodium dodecyl-sulfate; Exome Sequencing Project; The corrected QT interval of the ECG; using Bazett's formula; Noble; Ten Tusscher; The rapid delayed rectifier current; Noble and Panfilov; underlied in cardiac cells by hERG; mathematical model of a human ventricular action potential
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2013.11.072

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 >500ms, 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. 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. R148W alone produced a current similar to the WT (369±76nA (mean±SEM), n=13 versus 342±55nA in WT, n=13), while the co-expression of 1/2 WT+1/2 R148W lowered the current by 29% versus WT (243±35nA, 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 +20mV 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 323.5ms to 345ms was observed using the human cardiac ventricular myocyte model. 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. •The rare variant hERG/R148W was found in 1 adult cardiac sudden death and 2 SIDS.•This variant does not affect the trafficking or the kinetics of the hERG channel.•Equimolar expression of WT and mutant hERG reduced current by 29%.•Heterozygous carriers of this variant may be at risk of cardiac sudden death.