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

Unlabelled: 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.