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A new C-terminal hERG mutation A915fs+47X associated with symptomatic LQT2 and auditory-trigger syncope.: New LQT2-related hERG mutation A915fs+47X

Abstract : BACKGROUND: A novel mutation of hERG (A915fs+47X) was discovered in a 32-year-old woman with torsades de pointes, long QTc interval (515 ms), and syncope upon auditory trigger. OBJECTIVE: We explored whether the properties of this mutation could explain the pathology. METHODS: Whole-cell A915fs+47X (del) and wild-type (WT) currents were recorded in transiently transfected COS7 cells or Xenopus oocytes. Western blots and sedimentation analysis of del/WT hERG were used to analyze protein expression, assembly, and trafficking. RESULTS: The tail current density at -40 mV after a 2-s depolarization to +40 mV in COS7 cells expressing del was 36% of that for WT. Inactivation was 1.9-fold to 2.8-fold faster in del versus WT between -60 and +60 mV. In the range -60 to -10 mV, we found that a nondeactivating fraction of current was increased in del at the expense of a rapidly deactivating fraction, with a slowly deactivating fraction being unchanged. In Xenopus oocytes, expression of del alone produced 38% of WT currents, whereas coexpression of 1/2 WT + 1/2 del produced 49.8%. Furthermore, the expression of del protein at the cell surface was reduced by about 50%. This suggests that a partial trafficking defect of del contributes to the reduction in del current densities and to the dominant negative effect when coexpressed with WT. In model simulations, the mutation causes a 10% prolongation of action potential duration. CONCLUSION: Decreased current levels caused by a trafficking defect may explain the long QT syndrome observed in our patient.
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https://www.hal.inserm.fr/inserm-00325603
Contributor : Georges Christé <>
Submitted on : Friday, October 10, 2008 - 10:11:37 AM
Last modification on : Monday, July 20, 2020 - 1:06:04 PM
Long-term archiving on: : Friday, June 4, 2010 - 11:56:34 AM

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Georges Christé, Olivier Thériault, Mohamed Chahine, Gilles Millat, Claire Rodriguez-Lafrasse, et al.. A new C-terminal hERG mutation A915fs+47X associated with symptomatic LQT2 and auditory-trigger syncope.: New LQT2-related hERG mutation A915fs+47X. Heart Rhythm, Elsevier, 2008, 5 (11), pp.1577-86. ⟨10.1016/j.hrthm.2008.08.031⟩. ⟨inserm-00325603⟩

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