Substitution of a conserved alanine in the domain IIIS4-S5 linker of the cardiac sodium channel causes long QT syndrome

Objective: Congenital long QT syndrome type 3 (LQT3) is an inherited cardiac arrhythmia disorder due to mutations in the cardiac sodium channel gene, SCN5A. Although most LQT3 mutations cause a persistent sodium current, increasing diversity in the disease mechanism is shown. Here we present the electrophysiological properties of the A1330T sodium channel mutation (DIIIS4-S5 linker). Like the A1330P, LQT3 mutation, A1330T, causes LQT3 in the absence of a persistent current. Methods: A1330T, A1330P and wild-type sodium channels were expressed in HEK-293 cells and characterized using the whole-cell configuration of the patch-clamp technique. Results: The A1330T mutation shifts positively the voltage-dependence of inactivation and speeds recovery from inactivation. Measurements of sodium window (I-Na,I- window) currents revealed a positive shift of the I-Na,I- window voltage range for both 1330 mutants, with in addition an increase in I-Na,I- window magnitude for the A1330P mutant. Action potential (AP) clamp experiments revealed that these changes in I-Na,I- window properties cause an increased inward current during the initial part of phase 4 repolarization of the AP. Conclusions: Our findings indicate that the alanine at position 1330 in the DIIIS4-S5 linker of the cardiac sodium channel has a role in channel fast inactivation. Substitution by a threonine shifts the voltage range of I-Na,I- window activity to more positive potentials. Here the counter-acting effect of outward K+ current is reduced and may delay AP repolarization, explaining the LQT3 phenotype. (C) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.