Novel molecular basis underlying lethal arrhythmic syndrome due to mutations in cardiac Na/Ca exchanger gene

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18H02808
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: 蒔田 直昌 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)
• Co-Investigator(Kenkyū-buntansha): 牧山 武 京都大学, 医学研究科, 特定講師 (30528302)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 致死性不整脈 / Na-Ca交換体 / 早期再分極症候群 / QT短縮症候群 / ゲノム編集 / ノックインマウス / パッチクランプ / コンピュータシミュレーション

Outline of Annual Research Achievements

本研究は、心筋イオン輸送体に焦点を当てて致死性不整脈の新たな病因を探求することである。致死性不整脈の原因究明はQT延長症候群以外では十分に進んでおらず、イオンチャネルを候補遺伝子とする従来の手法で新たな病因を見出すのは困難である。申請者は最近、心電図QT時間の短縮と早期再分極(J波）を特徴とする致死性不整脈の蘇生症例において網羅的遺伝子解析を行い、心筋Na-Ca交換体（NCX）遺伝子の変異を同定した。フランスとの共同研究で、同様の臨床像を有し同一遺伝子上の変異を有する家系をさらに4家系同定した。最大の家系において全ゲノムシークエンスを行い、他の疾患遺伝子の関与が除外された。in vitro機能解析手法でNCXの機能低下を認め、活動電位のコンピュータシミュレーションではQT短縮が再現された。さらに、in vivoで機能異常を解明するために、ゲノム編集で変異導入ノックインマウス作成した。マウスは安静時心電図・心エコーなどに異常はないが、バースト電気刺激で心室性頻拍が誘発された。現在、単離心室筋細胞の活動電位とNCX電流を測定している。これまで得られた研究成果をもとに、NCX変異による細胞内Ca制御異常という新たな疾患概念を確立し、心臓突然死の予知予防に応用する。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Impact of the T-wave characteristics on distinguishing arrhythmogenic right ventricular cardiomyopathy from healthy children (2021)
  • Author(s): Imamura T, Sumitomo N, Muraji S, Yasuda K, Nishihara E, Iwamoto M, Tateno S, Doi S, Hata T, Kogaki S, Horigome H, Ohno S, Ichida F, Nagashima M, Makiyama T, Yoshinaga M.
  • Journal Title: International Journal of Cardiology Volume: 323 Pages: 168～174
  • DOI: 10.1016/j.ijcard.2020.08.088
  • Peer Reviewed
• [Journal Article] Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls (2020)
  • Author(s): Walsh R, Lahrouchi N, Ishikawa T, Makita N, Bezzina C. R et al.
  • Journal Title: Genetics in Medicine Volume: 23 Pages: 47～58
  • DOI: 10.1038/s41436-020-00946-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families (2020)
  • Author(s): Wijeyeratne Y. D, Ishikawa T, Makita, N, Aiba, T, Behr ER et al.
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 13 Pages: e002911
  • DOI: 10.1161/CIRCGEN.120.002911
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiac Emerinopathy: A Nonsyndromic Nuclear Envelopathy With Increased Risk of Thromboembolic Stroke Due to Progressive Atrial Standstill and Left Ventricular Noncompaction (2020)
  • Author(s): Ishikawa T, Mishima H, Barc J, Yoshiura KI, Schott JJ, Makita N et al.
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 13 Pages: e008712
  • DOI: 10.1161/CIRCEP.120.008712
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome (2020)
  • Author(s): Lahrouchi, N, Ishikawa T, Makita N, Bezzina CR et al.
  • Journal Title: Circulation Volume: 142 Pages: 324～338
  • DOI: 10.1161/CIRCULATIONAHA.120.045956
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Propranolol Attenuates Late Sodium Current in a Long QT Syndrome Type 3-Human Induced Pluripotent Stem Cell Model (2020)
  • Author(s): Hirose S, Makiyama T, Melgari D, Yamamoto Y, Wuriyanghai Y, Yokoi F, Nishiuchi S, Harita T, Hayano M, Kohjitani H, Gao J, Kashiwa A, Nishikawa M, Wu J, Yoshimoto J, Chonabayashi K, Ohno S, Yoshida Y, Horie M, Kimura T.
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 761
  • DOI: 10.3389/fcell.2020.00761
  • Peer Reviewed / Open Access
• [Journal Article] Telethonin variants found in Brugada syndrome, J‐wave pattern ECG, and ARVC reduce peak Na v 1.5 currents in HEK‐293 cells (2020)
  • Author(s): Turker I, Makiyama T, Ueyama T, Shimizu A, Yamakawa M, Chen PS, Vatta M, Horie M, Ai T.
  • Journal Title: Pacing and Clinical Electrophysiology Volume: 43 Pages: 838～846
  • DOI: 10.1111/pace.13996
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Erratum to “Optical Recording of Action Potentials in Human Induced Pluripotent Stem Cell-Derived Cardiac Single Cells and Monolayers Generated from Long QT Syndrome Type 1 Patients” (2020)
  • Author(s): Takaki T, Inagaki A, Chonabayashi K, Inoue K, Miki K, Ohno S, Makiyama T, Horie M, Yoshida Y.
  • Journal Title: Stem Cells International Volume: 2020 Pages: 1～2
  • DOI: 10.1155/2020/8765895
  • Peer Reviewed / Open Access
• [Presentation] Modeling Inherited Arrhythmias Associated with Ryanodine Receptor Dysfunction using iPS Cells (2021)
  • Author(s): Makiyama T, Gao J, Yamamoto Y, Ishikawa T, Makita N, Kimura T et al.
  • Organizer: 第85回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Development of an Oligonucleotide-Based Therapeutic Approach for Calmodulinopathy (2021)
  • Author(s): Makiyama T, Yamamoto Y, Ishikawa T, Makita N, Horie M, Kimura T et al.
  • Organizer: 第85回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Genetic Risks of Sudden Death in Brugada Syndrome (2020)
  • Author(s): Makita N.
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] iPS Cell-Based Inherited Arrhythmia Disease Modeling. iPSCs: Limitations and Future challenges. Cardiac Arrhythmias (2020)
  • Author(s): Makiyama T.
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Cardiac Emerinopathy, Novel Non-syndromic X-linked Left Ventricular Noncompaction Associated with Progressive Atrial Conduction Disturbance (2020)
  • Author(s): Ishikawa T, Aiba T, Ohno S, Yoshiura K, Makita N et al
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Preclinical Proof-of-Concept Study: Antisense-mediated Knockdown of CALM as a Therapeutic Strategy for Calmodulinopathy (2020)
  • Author(s): Yamamoto Y, Makiyama T, Kondo Y, Iriyama Y, Ishikawa R, Kimura T et al.
  • Organizer: European Society of Cardiology Congress 2020
  • Int'l Joint Research
• [Presentation] Inhibition of Late Sodium Current Attenuates Prolonged Action Potential Durations in CACNA1C-E1115K iPS Cell Model with Disrupted Cav1.2 ion Selectivity (2020)
  • Author(s): Kashiwa A, Makiyama T, Ishikawa T, Makita N, Kimura T et al.
  • Organizer: The Heart Rhythm Society's Annual Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] Clinical and genetic aspects of pediatric Brugada syndrome (2020)
  • Author(s): Imamura T, Makiyama T, Sumitomo N, Horie M et al.
  • Organizer: European Society of Cardiology Congress 2020
  • Int'l Joint Research
• [Remarks] 国立循環器病研究センター 創薬オミックス解析センター 研究プロジェクト
  • URL: http://www.ncvc.go.jp/omics/research/project03.html