title: SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome.
abstract: BACKGROUND
  Congenital long-QT syndrome (LQTS) is potentially lethal secondary to malignant ventricular arrhythmias and is caused predominantly by mutations in genes that encode cardiac ion channels. Nearly 25% of patients remain without a genetic diagnosis, and genes that encode cardiac channel regulatory proteins represent attractive candidates. Voltage-gated sodium channels have a pore-forming alpha-subunit associated with 1 or more auxiliary beta-subunits. Four different beta-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome.
  
  
  RESULTS
  We present a case of a 21-month-old Mexican-mestizo female with intermittent 2:1 atrioventricular block and a corrected QT interval of 712 ms. Comprehensive open reading frame/splice mutational analysis of the 9 established LQTS-susceptibility genes proved negative, and complete mutational analysis of the 4 Na(vbeta)-subunits revealed a L179F (C535T) missense mutation in SCN4B that cosegregated properly throughout a 3-generation pedigree and was absent in 800 reference alleles. After this discovery, SCN4B was analyzed in 262 genotype-negative LQTS patients (96% white), but no further mutations were found. L179F was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells that contained the stably expressed SCN5A-encoded sodium channel alpha-subunit (hNa(V)1.5). Compared with the wild-type, L179F-beta4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-beta4) increase in late sodium current consistent with the molecular/electrophysiological phenotype previously shown for LQTS-associated mutations.
  
  
  CONCLUSIONS
  We provide the seminal report of SCN4B-encoded Na(vbeta)4 as a novel LQT3-susceptibility gene.
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kaku
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Pedro
authors.initials: P
authors.lastname: Iturralde-Torres
authors.forename: Ajit
authors.initials: A
authors.lastname: Itty
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Carmen
authors.initials: C
authors.lastname: Valdivia
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ueda
authors.forename: Samuel
authors.initials: S
authors.lastname: Canizales-Quinteros
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Tusié-Luna
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D019943:Amino Acid Substitution; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000151:congenital / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values; D015222:Sodium Channels / Q000235:genetics*; D062585:Voltage-Gated Sodium Channel beta-4 Subunit
chemical_list: C477263:SCN4B protein, human; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D004247:DNA