title: Substitution of a conserved alanine in the domain IIIS4-S5 linker of the cardiac sodium channel causes long QT syndrome.
abstract: OBJECTIVE
  Congenital long QT syndrome type 3 (LQT3) is an inherited cardiac arrhythmia disorder due to mutations in the cardiac sodium channel gene, SCN5A. Although most LQT3 mutations cause a persistent sodium current, increasing diversity in the disease mechanism is shown. Here we present the electrophysiological properties of the A1330T sodium channel mutation (DIIIS4-S5 linker). Like the A1330P, LQT3 mutation, A1330T, causes LQT3 in the absence of a persistent current.
  
  
  METHODS
  A1330T, A1330P and wild-type sodium channels were expressed in HEK-293 cells and characterized using the whole-cell configuration of the patch-clamp technique.
  
  
  RESULTS
  The A1330T mutation shifts positively the voltage-dependence of inactivation and speeds recovery from inactivation. Measurements of sodium window (I(Na, window)) currents revealed a positive shift of the I(Na, window) voltage range for both 1330 mutants, with in addition an increase in I(Na, window) magnitude for the A1330P mutant. Action potential (AP) clamp experiments revealed that these changes in I(Na, window) properties cause an increased inward current during the initial part of phase 4 repolarization of the AP.
  
  
  CONCLUSIONS
  Our findings indicate that the alanine at position 1330 in the DIIIS4-S5 linker of the cardiac sodium channel has a role in channel fast inactivation. Substitution by a threonine shifts the voltage range of I(Na, window) activity to more positive potentials. Here the counter-acting effect of outward K+ current is reduced and may delay AP repolarization, explaining the LQT3 phenotype.
authors.affiliation: Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jeroen P P
authors.initials: JP
authors.lastname: Smits
authors.forename: Marieke W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Zahir A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.forename: Horst
authors.initials: H
authors.lastname: Wedekind
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
mesh_terms: D000293:Adolescent; D000328:Adult; D000409:Alanine / Q000235:genetics*; D002460:Cell Line; D017124:Conserved Sequence; D016757:Death, Sudden, Cardiac; D004594:Electrophysiology; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017434:Protein Structure, Tertiary; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D000409:Alanine