SCN4B-Encoded Sodium Channel &bgr;4 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 &agr;-subunit associated with 1 or more auxiliary &bgr;-subunits. Four different &bgr;-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 Nav&bgr;-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 &agr;-subunit (hNaV1.5). Compared with the wild-type, L179F-&bgr;4 caused an 8-fold (compared with SCN5A alone) and 3-fold (compared with SCN5A + WT-&bgr;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 Nav&bgr;4 as a novel LQT3-susceptibility gene.

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