Novel molecular basis underlying lethal arrhythmic syndrome due to mutations in cardiac Na/Ca exchanger gene
Project/Area Number |
18H02808
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 53020:Cardiology-related
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Research Institution | National Cardiovascular Center Research Institute |
Principal Investigator |
MAKITA Naomasa 国立研究開発法人国立循環器病研究センター, 研究所, 副所長 (00312356)
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Co-Investigator(Kenkyū-buntansha) |
牧山 武 京都大学, 医学研究科, 特定講師 (30528302)
渡邊 泰秀 浜松医科大学, 医学部, 教授 (50305380)
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Project Period (FY) |
2018-04-01 – 2021-03-31
|
Project Status |
Completed (Fiscal Year 2020)
|
Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
|
Keywords | 早期再分極症候群 / Na/Ca交換体 / 遺伝子変異 / 突然死 / ゲノム編集 / パッチクランプ / 致死性不整脈 / Na-Ca交換体 / QT短縮症候群 / ノックインマウス / コンピュータシミュレーション / J波症候群 / 心臓突然死 |
Outline of Final Research Achievements |
Comprehensive genetic screening of patients with early repolarization syndrome (ERS) identified six novel mutations in the cardiac Na/Ca exchanger(NCX1) gene. Whole-genome sequencing confirmed cosegregation of NCX1 mutations within two families. Mutant NCX1 cDNAs transiently transfected in HEK293 cells showed reduced 45Ca uptake and NCX1 current amplitudes associated with membrane trafficking defect. Programmed electrical stimulation of burst pacing mode at the right ventricular apex reproducibly elicited ventricular tachycardia in NCX1-L215H knock-in mice that were established by CRISPR/Cas9 genome editing, but not in wild type mice. These data demonstrated that the cardiac NCX1 is a novel gene responsible for ERS, which is characterized by J wave and predisposition to lethal ventricular arrhythmia.
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Academic Significance and Societal Importance of the Research Achievements |
心電図のJ波は長い間正常亜型と考えられてきた。最近J波を特徴とする特発性心室細動は、早期再分極症候群(ERS)という独立した致死性不整脈と認識されているが、未発症のERS患者とJ波陽性の健常人を心電図だけで鑑別することは困難である。本研究はこれまで未解明だったERSの新たな原因として、心筋Na/Ca 交換体(NCX1)の遺伝子異常を明らかにした。今後NCX1の変異と詳細な機能異常がさらに詳細に解明されれば、遺伝子解析結果に基づく心臓突然死のリスクを評価と層別化が可能になり、突然死の個別化予防医療の実現につながることが期待される。
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Report
(4 results)
Research Products
(107 results)
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Journal Title
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ISSN
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Year and Date
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