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

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. 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 Na-v beta-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-beta 4 caused an 8-fold ( compared with SCN5A alone) and 3-fold ( compared with SCN5A + WT-beta 4) 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(v beta)4 as a novel LQT3-susceptibility gene.