Phamacogenomic studies for the genetic basis for lethal arrhythmias
| Project/Area Number |
15590711
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
MAKITA Naomasa Hokkaido University, Graduate School of Medicine, Assistant Professor, 大学院・医学研究科, 助手 (00312356)
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| Co-Investigator(Kenkyū-buntansha) |
HORIE Minoru Shiga Medical University, Professor, 医学部, 教授 (90183938)
SHIMIZU Wataru National Cardiovascular Center, 心臓血管内科, 医長
SASAKI Koji Hokkaido University Hospital, 病院・医員 (30374317)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | lathal arrhythmia / ion channel / mutation / polymorphism / SCN5A / Brugada syndrome / Long QT syndrome / atrial standstill |
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| Research Abstract |
Genetic screening was performed in the genomic DNAs from normal volunteers (n=120), congenital long QT syndrome (cLQTS ; n=30), acquired long QT syndrome (aLQTS ; n=4), asymptomatic Brugada syndrome (aBS ; n=30), symptomatic Brugada syndrome (sBS ; n=37), progressive cardiac conduction disturbance (PCCD ; n=2), and atrial standstill (AS ; n=2).
We found a cardiac possatium channel gene KCNH2 mutation in cLQTS. Nine distinct mutations were found in cardiac Na channels genes (SCN5A) ; cLQTS(2/30), aLQTS(1/4), aBS(1/30), sBS(5/37), PCCD(1/2), and AS(1/2). Biophysical abnormalities of the eight SCN5A mutations were determined by site-directed mutagenesis and heterologous expression system using mammalian cultured cell tsA-201. Whole cell Na current were recorded by transient transfection of these mutant Na channels. 3 mutant channels responsible for cLQTS and aLQTS showed persistent Na current that is characteristic for other LQT3 mutant channels. 2 mutant channels out of 5 mutation of sBS and the AS mutant channel showed no observable current. The mutation responsible for aBS was a double mutation at the same exon of SCN5A, and showed loss-of function properties characteristic for BS.
We have identified two novel single nucleotide polymorphisms (SNP) in SCN5A. V1951L and L1988R. Allele frequencies determined by TaqMan PCR strategies was not significantly difference between normal group and Brugada syndrome group. Flecainide sensitivities of these SNPs were nearly identical to wild type Na channel, suggesting that these SNPs are unlikely to underlie differences in the sensitivities to Na channel blockers.
The double mutation identified in an aBS case is the first SCN5A mutation responsible for aBS (Yokoi et al. Heart Rhythm 2005). The mutation responsible for AS was the third SCN5A mutation reported so far. We found a concomitant SNP in the connexin 40 in this case, and now investigating the pathogenesis of atria-specific nature of this arrhythmia.
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Report
(3 results)
Research Products
(32 results)
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[Journal Article] Double SCN5A mutation underlying asymptomatic Brugada syndrome.2005
Author(s)
Yokoi H, Makita N, Sasaki K, Takagi Y, Okumura Y, Nishino T, Makiyama T, Kitabatake A, Horie M, Watanabe I, Tsutsui H.
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Journal Title
Heart Rhythm 2
Pages: 285-292
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline2004
Author(s)
Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Mental M, Makita N, Tanaka M, Fukushima K, Fujiwara T, Inoue Y, Yamakawa K.
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Journal Title
J Neurosci 24
Pages: 2690-2698
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] State-dependent blocking actions of azimilide dihydrochloride (NE-10064) on human cardiac Na^+ channels.2004
Author(s)
Miake J, Kurata Y, Iizuka K, Furuichi H, Manabe K, Sasaki N, Yamamoto Y, Hoshikawa Y, Taniguchi S, Yoshida A, Igawa O, Makita N, Shiota G, Nanba E, Ohgi S, Narahashi T, Hisatome I.
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Journal Title
Circ J. 68
Pages: 703-711
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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