Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation

Abstract

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia

“…The slower time to peak I Na (Fig. 5A) in our study indicates that the mutant channels require a more positive membrane potential to fully activate and more time to reach the membrane potential at which the maximum current amplitude occurs than WT channels, which might manifest on the ECG in a widening of the QRS in CCD [5,10,18,19]. However, the mechanisms by which the proband showed SSS and monomorphic VT but not BrS1, are unknown.…”

“…It has been proposed [18] that a rightward shift in the voltage dependence of the mutant sodium channel activation curve, as found with L1821fs/10 (Fig. 4A) is a common feature of CCD [5,9,10,19]. The slower time to peak I Na (Fig.…”

“…This discovery provides the fifth SCN5A mutation associated with multiple clinical phenotypes [7][8][9][10]. Generally, mutations in SCN5A that cause a decrease in peak I Na density appear to be associated with BrS1/CCD [3,5,9].…”

“…To date, at least 4 mutations in the cardiac sodium channel have been identified whereby the same mutation precipitated multiple different disease phenotypes [7][8][9][10]. An insertion of an aspartic acid residue in the C-terminus of SCN5A (1795insD) can result in either BrS1 or LQT3 [8].…”

“…The mutation of glycine to arginine (G1406R in the original publication, G1408R by present numbering) in the DIII/S5 to DIII/S6 region resulted in either BrS1 or ICCD in several families [9]. The deletion of a lysine in the III-IV linker of SCN5A (ΔK1500) is associated with BrS1, LQT3 and ICCD [10]. A replacement of glutamic acid by the basic residue lysine (E161K) in the DI/S2 transmembrane region contributes to SSS, CCD and BrS1 [7].…”