title: Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.
abstract: BACKGROUND
  Congenital long-QT syndrome (LQTS) is an inherited condition of abnormal cardiac excitability characterized clinically by an increased risk of ventricular tachyarrhythmias. One form, LQT3, is caused by mutations in the cardiac voltage-dependent sodium channel gene, SCN5A. Only 5 SCN5A mutations have been associated with LQTS, and more work is needed to improve correlations between SCN5A genotypes and associated clinical syndromes.
  
  
  RESULTS
  We researched a 3-generation white family with autosomal dominant LQTS who exhibited a wide clinical spectrum from mild bradycardia to sudden death. Molecular genetic studies revealed a single nucleotide substitution in SCN5A exon 28 that caused the substitution of Glu1784 by Lys (E1784K). The mutation occurs in a highly conserved domain within the C-terminus of the cardiac sodium channel containing multiple, negatively charged amino acids. Two-electrode voltage-clamp recordings of a recombinant E1784K mutant channel expressed in Xenopus oocytes revealed a defect in fast inactivation characterized by a small, persistent current during long membrane depolarizations. Coexpression of the mutant with the human sodium channel beta1-subunit did not affect the persistent current, even though we did observe shifts in the voltage dependence of steady-state inactivation. Neutralizing multiple, negatively charged residues in the same region of the sodium channel C-terminus did not cause a more severe functional defect.
  
  
  CONCLUSIONS
  We characterized the genetics and molecular pathophysiology of a novel SCN5A sodium channel mutation, E1784K. The functional defect exhibited by the mutant channel causes delayed myocardial repolarization, and our data on the effects of multiple charge neutralizations in this region of the C-terminus suggest that the molecular mechanism of channel dysfunction involves an allosteric rather than a direct effect on channel gating.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: D W
authors.initials: DW
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Alings
authors.forename: F
authors.initials: F
authors.lastname: Fish
authors.forename: M
authors.initials: M
authors.lastname: Wathen
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
authors.forename: A L
authors.initials: AL
authors.lastname: George
mesh_terms: D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017124:Conserved Sequence; D017931:DNA Primers; D003645:Death, Sudden; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000737:chemistry; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000502:physiology; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000494:pharmacology; D014981:Xenopus
chemical_list: D017931:DNA Primers; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D013779:Tetrodotoxin