SCN4B-encoded sodium channel beta4 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.


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.
Medeiros-Domingo
Argelia
A
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México.
Kaku
Toshihiko
T
Tester
David J
DJ
Iturralde-Torres
Pedro
P
Itty
Ajit
A
Ye
Bin
B
Valdivia
Carmen
C
Ueda
Kazuo
K
Canizales-Quinteros
Samuel
S
Tusié-Luna
Maria Teresa
MT
Makielski
Jonathan C
JC
Ackerman
Michael J
MJ
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
C477263:SCN4B protein, human; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D004247:DNA