Medeiros Domingo, Argelia; Kaku, Toshihiko; Tester, David J; Iturralde-Torres, Pedro; Itty, Ajit; Ye, Bin; Valdivia, Carmen; Ueda, Kazuo; Canizales-Quinteros, Samuel; Tusié-Luna, Maria Teresa; Makielski, Jonathan C.; Ackerman, Michael J. (2007). SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation, 116(2), pp. 134-142. Lippincott Williams & Wilkins 10.1161/CIRCULATIONAHA.106.659086
Full text not available from this repository.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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology |
UniBE Contributor: |
Medeiros Domingo, Argelia |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0009-7322 |
Publisher: |
Lippincott Williams & Wilkins |
Language: |
English |
Submitter: |
Argelia Medeiros Domingo |
Date Deposited: |
13 Jun 2014 17:30 |
Last Modified: |
05 Dec 2022 14:28 |
Publisher DOI: |
10.1161/CIRCULATIONAHA.106.659086 |
PubMed ID: |
17592081 |
URI: |
https://boris.unibe.ch/id/eprint/42288 |
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