Identification of novel factor in hereditary sinus bradycardia and its application to preventive medicine

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09111
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Satoru Yamazaki 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (70348796)
• Co-Investigator(Kenkyū-buntansha): 北風 政史 国立研究開発法人国立循環器病研究センター, 研究開発基盤センター, 部長 (20294069)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 臨床遺伝 / 洞性徐脈 / ゲノム / 循環器 / 刺激伝導組織

Outline of Final Research Achievements

Normal heart rate and rhythm are essential for proper heart function. As disorders of impulse generation and/or propagation in the cardiac conduction system culminate in symptomatic, life-threatening bradyarrhythmias, the ion channels responsible for these phenomena represent promising therapeutic targets. We describe a family affected with hereditary sinus bradycardia. Genetic analysis revealed a novel mutation in KCNJ3, which encodes a subunit of the acetylcholine-activated potassium channel (IKACh channel). The mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of G protein-coupled receptor stimulation. The selective IKACh channel blocker NIP-151 repressed the current increase and improved all bradyarrhythmia phenotypes in zebrafish harbouring the mutation. We thus identified the KCNJ3 mutation as responsible for these bradyarrhythmias and propose that selective IKACh channel blockers may be a valuable therapeutic approach.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

遺伝性徐脈性不整脈の新たな原因として、IKAChチャネルの新規遺伝子変異を同定し、本チャネルの異常活性化が徐脈性不整脈の原因となることを見出した。本チャネルの選択的阻害薬は異常活性化を示す変異型チャネルに対しても高い阻害活性を示し、同チャネル変異を導入した疾患モデル動物においても有効性を示したことから、徐脈性不整脈に対する新規の分子標的治療薬になり得ることが示唆された