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Cardiovascular Research 2003 57(4):1072-1078; doi:10.1016/S0008-6363(02)00838-6
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics

W.Antoinette Groenewegena,*, Connie R. Bezzinab,f, J.Peter van Tintelenc,d, Theo M. Hoorntjee, Marcel M.A.M. Mannensf, Arthur A.M. Wildeb,g, Habo.J. Jongsmaa and Martin B. Rooka

aDepartment of Medical Physiology, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands
bExperimental and Molecular Cardiology Group, AMC Amsterdam, Amsterdam, The Netherlands
cDepartment of Clinical Genetics, UMC Utrecht, Utrecht, The Netherlands
dUniversity Hospital Groningen, Groningen, The Netherlands
eDepartment of Paediatrics, St. Antonius Ziekenhuis, Nieuwegein, The Netherlands
fDepartment of Clinical Genetics, AMC Amsterdam, Amsterdam, The Netherlands
gThe Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands

* Corresponding author. Tel.: +31-30-253-8900; fax: +31-30-253-9036. groenewegen{at}med.uu.nl

* For this manuscript Dr. R.F. Bosch acted as Guest Editor.

The Long QT3 syndrome is associated with mutations in the cardiac sodium channel gene SCN5A. Objective: The aim of the present study was the identification and functional characterization of a mutation in a family with the long QT3 syndrome. Methods: The human cardiac sodium channel gene SCN5A was screened for mutations by single-stranded conformation polymorphism. The functional consequences of mutant sodium channels were characterized after expressing mutant and wild-type cRNAs in Xenopus oocytes by two-electrode voltage clamp measurements. Results: SCN5A screening revealed an A->G substitution at codon 1768, close to the C-terminal end of domain IVS6, which changes an isoleucine to a valine. Functional expression of mutant I1768V-channels in Xenopus oocytes showed that the voltage-dependence and slope factors of activation and inactivation were unchanged compared to wild-type channels. No difference in persistent TTX-sensitive current could be detected between wild-type and I1768V channels, a channel feature often increased in LQT3 mutants. However, I1768V mutant channels recovered faster from inactivation (2.4 times) than wild-type channels and displayed less slow inactivation. Conclusions: We postulate that severe destabilization of the inactivated state leads to increased arrhythmogenesis and QT prolongation in I1768V mutation carriers in the absence of a persistent inward sodium current.

KEYWORDS Biology; Arrhythmia (mechanisms); Long QT syndrome; Na-channel


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