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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: UNLABELLED, OBJECTIVE, METHODS, RESULTS. Meshes: Adolescent, Adult, Child, DNA Mutational Analysis, Death, Sudden, Cardiac, Electrocardiography, Female, Humans, Long QT Syndrome, Male, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Pedigree, Sodium Channels.
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Does a novel LQT3 mutation implicate the human cardiac sodium channel domain IVS6 in inactivation kinetics? Context: The Long QT3 syndrome is associated with mutations in the cardiac sodium channel gene SCN5A. The aim of the present study was the identification and functional characterization of a mutation in a family with the long QT3 syndrome. 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. 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.
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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. Final Decision: yes