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http://purl.uniprot.org/citations/17592081http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17592081http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17592081http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.106.659086"xsd:string
http://purl.uniprot.org/citations/17592081http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.106.659086"xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Ueda K."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Ueda K."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Ye B."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Ye B."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Tusie-Luna M.T."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Tusie-Luna M.T."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Kaku T."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Kaku T."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Makielski J.C."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Makielski J.C."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Medeiros-Domingo A."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Medeiros-Domingo A."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Canizales-Quinteros S."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Canizales-Quinteros S."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Valdivia C."xsd:string
http://purl.uniprot.org/citations/17592081http://purl.uniprot.org/core/author"Valdivia C."xsd:string
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