PMID- 10377081 OWN - NLM STAT- MEDLINE DCOM- 19990708 LR - 20190623 IS - 1524-4539 (Electronic) IS - 0009-7322 (Linking) VI - 99 IP - 24 DP - 1999 Jun 22 TI - Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. PG - 3165-71 AB - 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. METHODS AND 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. FAU - Wei, J AU - Wei J AD - Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. FAU - Wang, D W AU - Wang DW FAU - Alings, M AU - Alings M FAU - Fish, F AU - Fish F FAU - Wathen, M AU - Wathen M FAU - Roden, D M AU - Roden DM FAU - George, A L Jr AU - George AL Jr LA - eng GR - HL46681/HL/NHLBI NIH HHS/United States GR - NS32387/NS/NINDS NIH HHS/United States GR - T32 DK07569/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Circulation JT - Circulation JID - 0147763 RN - 0 (DNA Primers) RN - 0 (NAV1.5 Voltage-Gated Sodium Channel) RN - 0 (SCN5A protein, human) RN - 0 (Sodium Channels) RN - 4368-28-9 (Tetrodotoxin) SB - IM MH - Adolescent MH - Animals MH - Base Sequence MH - Cloning, Molecular MH - Conserved Sequence MH - DNA Primers MH - Death, Sudden MH - Electrocardiography MH - Electrophysiology MH - Female MH - Humans MH - Long QT Syndrome/*congenital/diagnosis/*genetics MH - Male MH - Membrane Potentials/drug effects/physiology MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - Myocardium/chemistry MH - NAV1.5 Voltage-Gated Sodium Channel MH - Oocytes/physiology MH - Pedigree MH - *Point Mutation MH - Polymorphism, Single-Stranded Conformational MH - Protein Structure, Tertiary MH - Sequence Homology, Amino Acid MH - Sodium Channels/chemistry/*genetics/metabolism MH - Structure-Activity Relationship MH - Tetrodotoxin/pharmacology MH - Xenopus EDAT- 1999/06/22 10:00 MHDA- 2001/03/28 10:01 CRDT- 1999/06/22 10:00 PHST- 1999/06/22 10:00 [pubmed] PHST- 2001/03/28 10:01 [medline] PHST- 1999/06/22 10:00 [entrez] AID - 10.1161/01.cir.99.24.3165 [doi] PST - ppublish SO - Circulation. 1999 Jun 22;99(24):3165-71. doi: 10.1161/01.cir.99.24.3165.