SCN4B-encoded sodium channel β4 subunit in congenital long-QT syndrome

Argelia Medeiros-Domingo, Toshihiko Kaku, David J. Tester, Pedro Iturralde-Torres, Ajit Itty, Bin Ye, Carmen Valdivia, Kazuo Ueda, Samuel Canizales-Quinteros, Maria Teresa Tusié-Luna, Jonathan C. Makielski, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

268 Scopus citations


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 α-subunit associated with 1 or more auxiliary β-subunits. Four different β-subunits have been described. All are detectable in cardiac tissue, but none have yet been linked to any heritable arrhythmia syndrome. METHODS AND 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 Navβ-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 α-subunit (hNaV1.5). Compared with the wild-type, L179F-β4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-β4) 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 Navβ4 as a novel LQT3-susceptibility gene.

Original languageEnglish (US)
Pages (from-to)134-142
Number of pages9
Issue number2
StatePublished - Jul 2007


  • Genetics
  • Ion channels
  • Long-QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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