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Novel G1481V and Q1491H SCN5A mutations linked to long QT syndrome destabilize the Nav1.5 inactivation state
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  • Quentin Plumereau,
  • Olivier Theriault,
  • Valerie Pouliot,
  • Adrien Moreau,
  • Elodie Morel,
  • Veronique Fressart,
  • Isabelle Denjoy,
  • Antoine Delinière,
  • Francis BESSIERE,
  • Philippe Chevalier,
  • Tamer Gamal El-Din,
  • Mohamed Chahine
Quentin Plumereau
Laval University Faculty of Medicine
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Olivier Theriault
Laval University Faculty of Medicine
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Valerie Pouliot
Laval University Faculty of Medicine
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Adrien Moreau
Laval University Faculty of Medicine
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Elodie Morel
Hopices Civils de Lyon
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Veronique Fressart
Centre de génétique moléculaire et chromosomique,
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Isabelle Denjoy
Hôpital Bichat - Claude-Bernard Service de Cardiologie
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Antoine Delinière
Hopital Cardio-vasculaire et Pneumologique Louis Pradel
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Francis BESSIERE
Hopital Louis Pradel
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Philippe Chevalier
Hopital Cardiologique
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Tamer Gamal El-Din
University of Washington
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Mohamed Chahine
Laval University Faculty of Medicine
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Abstract

BACKGROUND: Nav1.5, which is encoded by the SCN5A gene, is the predominant voltage-gated Na+ channel in the heart. Several mutations of this gene have been identified and have been reported to be involved in several cardiac rhythm disorders, including type 3 long QT syndrome (LQT3), that can cause sudden cardiac death. We analyzed the biophysical properties of two novel variants of the Nav1.5 channel (Q1491H and G1481V) detected in 5- and 12-week-old infants diagnosed with a prolonged QT interval. METHODS: The Nav1.5 wild-type (WT) and the Q1491H and G1481V mutant channels were reproduced in vivo. WT or the mutant channels were co-transfected in HEK 293 cells with the beta 1 regulatory subunit. Na+ currents were recorded using the whole-cell configuration of the patch-clamp technique. RESULTS: The Q1491H mutant channel exhibited a lower current density, a persistent Na+ current, an enhanced window current due to a +20-mV shift of steady-state inactivation, a +10-mV shift of steady-state activation, a faster onset of slow inactivation, and a recovery from fast inactivation with fast and a slow time constants of recovery. The G1481V mutant channel exhibited an increase in current density and a +7-mV shift of steady-state inactivation. The observed defects are characteristic of gain-of-function mutations typical of LQT3. DISCUSSION AND CONCLUSION: The 5- and 12-week-old infants displayed prolonged QT intervals. Our analyses of the Q1491H and G1481V mutations correlated with the clinical diagnosis. The observed biophysical dysfunctions associated with both mutations were most likely responsible for the sudden deaths of the two infants.