21 research outputs found
Association of New Loci Identified in European Genome-Wide Association Studies with Susceptibility to Type 2 Diabetes in the Japanese
Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies. locus, had nominal association with type 2 diabetes in the present Japanese samples (P<0.05). locus may be common locus for type 2 diabetes across different ethnicities
Augmented vasodilator response to l -arginine after coronary angioplasty may attenuate restenosis
Impaired alveolization in mice deficient in membrane-type matrix metalloproteinase 1 (MT1-MMP)
Surgical treatment for thoracoabdominal intra-aortic thrombus with multiple infarctions: a case report
Rescue of Pulmonary Hypertension with an Oral Sulfonamide Antibiotic Sulfisoxazole by Endothelin Receptor Antagonistic Actions
Efficacy and Safety Evaluation of Tolvaptan on Management of Fluid Balance after Cardiovascular Surgery Using Cardiopulmonary Bypass
Essential role of macrophage migration inhibitory factor (MIF) in the pathogenesis of dextran sulfate sodium-induced colitis in mice: Amelioration of colocecal damage by anti-MIF antibody
Escitalopram versus paroxetine controlled release in major depressive disorder: a randomized trial
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.
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