TY - JOUR
T1 - SCN4B-encoded sodium channel β4 subunit in congenital long-QT syndrome
AU - Medeiros-Domingo, Argelia
AU - Kaku, Toshihiko
AU - Tester, David J.
AU - Iturralde-Torres, Pedro
AU - Itty, Ajit
AU - Ye, Bin
AU - Valdivia, Carmen
AU - Ueda, Kazuo
AU - Canizales-Quinteros, Samuel
AU - Tusié-Luna, Maria Teresa
AU - Makielski, Jonathan C.
AU - Ackerman, Michael J.
PY - 2007/7
Y1 - 2007/7
N2 - 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.
AB - 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.
KW - Genetics
KW - Ion channels
KW - Long-QT syndrome
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UR - http://www.scopus.com/inward/citedby.url?scp=34447307435&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.106.659086
DO - 10.1161/CIRCULATIONAHA.106.659086
M3 - Article
C2 - 17592081
AN - SCOPUS:34447307435
SN - 0009-7322
VL - 116
SP - 134
EP - 142
JO - Circulation
JF - Circulation
IS - 2
ER -