Document Detail

The variant hERG/R148W associated with LQTS is a mutation that reduces current density on co-expression with the WT.
MedLine Citation:
PMID:  24334129     Owner:  NLM     Status:  Publisher    
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>500ms, atrio-ventricular 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±76nA (mean±SEM), n=13 versus 342±55nA in WT, n=13), while the coexpression 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 coexpression 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.
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.
Asma Mechakra; Yohann Vincent; Philippe Chevalier; Gilles Millat; Eckhard Ficker; Marek Jastrzebski; Hugo Poulin; Valérie Pouliot; Mohamed Chahine; Georges Christé
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-12-12
Journal Detail:
Title:  Gene     Volume:  -     ISSN:  1879-0038     ISO Abbreviation:  Gene     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7706761     Medline TA:  Gene     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013. Published by Elsevier B.V.
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