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 (∆K1500) 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 ∆K1500 mutant channel. The mutation shifted the potential for half inactivation (V 1/2 h ∞ ) to more negative values and reduced its voltage dependence consistent with a reduction of inactivation valence of 1. The shift in inactivation was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). The potential for half activation (V 1/2 m) was shifted to more positive potentials, and its voltage dependence reduced by 50% in the ∆K1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (∆ charge, -1, -2). 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 ∆K1500 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.

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

“…In our patient, the phenotype appears to be more consistent with LQTS and conduction disease. SCN5A has been shown to have considerable phenotypic variability, with reports of both Brugada and LQT3 phenotypes with a single genotype (26)(27)(28)(29)(30)(31). The underlying electrophysiological explanation for this may involve differential effects on the fast and slow components of sodium channel inactivation (31).…”

Congenital long QT syndrome of particularly malignant course connected with so far unknown mutation in the sodium channel SCN5A gene

“…Interestingly, Grant et al [10] described a family with sudden death and features resembling LQTS, Brugada syndrome, and conduction system disease at the same time. In this family, K1500del, also located in the intracellular linker DIII-DIV, accounted for the complex phenotype.…”

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

“…When examining the effect of the SCN5a-1798insD mutation in two strains of mice, Remme and colleagues noted that 129P2 mice have a more severe phenotype than FVB/N mice carrying the same mutation [8]. This observation echoes clinical findings that disease expression varies markedly even within the same family [9][10][11]. Finally, fundamental differences in the basic physiology of humans and rodents, such as heart rate, often overwhelm and mask the pro-arrhythmic consequences of channelopathies.…”