Long QT syndrome type 3 (GoF) & Brugada syndrome type 1 (LoF)
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 28-exon gene spanning approximately 80 kb at chromosome 3p22.2 adjacent to SCN10A and SCN11A, encoding a 2,016-residue pore-forming alpha subunit with four homologous six-transmembrane repeats and a cysteine residue (Cys373) in the domain I pore loop that renders Nav1.5 relatively resistant to tetrodotoxin.
Cellular & Tissue Expression Profile: Abundantly expressed at intercalated discs and lateral sarcolemmal membranes of atrial and ventricular cardiac myocytes as well as the His-Purkinje specialized conduction system and gastrointestinal interstitial cells of Cajal.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Mediates the rapid inward Na+ current (INa) responsible for the steep phase 0 upstroke of the cardiac action potential and rapid impulse propagation across the myocardium, followed by fast inactivation within milliseconds via the domain III–IV linker IFM motif.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Gain-of-function mutations (such as the classic p.Lys1505_Gln1507del KPQ deletion) disrupt fast inactivation and produce a persistent late sodium current (INa,L) causing congenital Long QT syndrome type 3 (LQT3), whereas loss-of-function variants reduce peak INa density and cause Brugada syndrome type 1, progressive cardiac conduction disease (Lev-Lenegre syndrome), and sick sinus syndrome.
Therapeutic & Clinical Pharmacology: Targeted by Class I antiarrhythmic sodium channel blockers (flecainide, lidocaine, mexiletine, quinidine) and late-sodium current inhibitors (ranolazine) used to shorten the QT interval in LQT3 patients.