title: A sodium channel pore mutation causing Brugada syndrome.
abstract: BACKGROUND
  Brugada and long QT type 3 syndromes are linked to sodium channel mutations and clinically cause arrhythmias that lead to sudden death. We have identified a novel threonine-to-isoleucine missense mutation at position 353 (T353I) adjacent to the pore-lining region of domain I of the cardiac sodium channel (SCN5A) in a family with Brugada syndrome. Both male and female carriers are symptomatic at young ages, have typical Brugada-type electrocardiogram changes, and have relatively normal corrected QT intervals.
  
  
  OBJECTIVE
  To characterize the properties of the newly identified cardiac sodium channel (SCN5A) mutation at the cellular level.
  
  
  RESULTS
  Using whole-cell voltage clamp, we found that heterologous expression of SCN5A containing the T353I mutation resulted in 74% +/- 6% less peak macroscopic sodium current when compared with wild-type channels. A construct of the T353I mutant channel fused with green fluorescent protein failed to traffic properly to the sarcolemma, with a large proportion of channels sequestered intracellularly. Overnight exposure to 0.1 mM mexiletine, a Na(+) channel blocking agent, increased T353I channel trafficking to the membrane to near normal levels, but the mutant channels showed a significant late current that was 1.6% +/- 0.2% of peak sodium current at 200 ms, a finding seen with long QT mutations.
  
  
  CONCLUSIONS
  The clinical presentation of patients carrying the T353I mutation is that of Brugada syndrome and could be explained by a cardiac Na(+) channel trafficking defect. However, when the defect was ameliorated, the mutated channels had biophysical properties consistent with long QT syndrome. The lack of phenotypic changes associated with the long QT syndrome could be explained by a T353I-induced trafficking defect reducing the number of mutant channels with persistent currents present at the sarcolemma.
authors.affiliation: Division of Cardiology, Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, Georgia 30033, USA.
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Pfahnl
authors.forename: Prakash C
authors.initials: PC
authors.lastname: Viswanathan
authors.forename: Raul
authors.initials: R
authors.lastname: Weiss
authors.forename: Lijuan L
authors.initials: LL
authors.lastname: Shang
authors.forename: Shamarendra
authors.initials: S
authors.lastname: Sanyal
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shusterman
authors.forename: Cari
authors.initials: C
authors.lastname: Kornblit
authors.forename: Barry
authors.initials: B
authors.lastname: London
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000200:Action Potentials; D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D006329:Heart Conduction System / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels