Key result
Novel SCN4B mutation increases late sodium current ~3-fold, identifying it as a new LQT3 gene.
Why the study?
Nearly 25% of congenital long-QT syndrome patients remain without a genetic diagnosis, and genes encoding cardiac channel regulatory proteins are candidate causes.
Case Report (n=263)
This study provides the first evidence that SCN4B-encoded Na(vbeta)4 is a novel susceptibility gene for LQT3, with the L179F mutation significantly increasing late sodium current.
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(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.
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Medeiros‐Domingo et al. (2007) conducted a case report in Congenital long-QT syndrome (n=263). SCN4B L179F mutation vs. Wild-type SCN4B was evaluated on Late sodium current (3-fold increase). The SCN4B L179F missense mutation was identified as a novel LQT3-susceptibility gene, causing a 3-fold increase in late sodium current compared to wild-type.
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