Molecular pathogenesis of heart failure and arrhythmia caused by gene abnormalities

• Project/Area Number: 16H05296
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KIMURA Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 遺伝学 / 遺伝子 / ゲノム / 循環器・高血圧 / 生体分子

Outline of Final Research Achievements

Targeted sequencing system for disease genes of hereditary cardiomyopathy and/or hereditary arrhythmia was developed. RBM20 mutations in dilated cardiomyopathy were demonstrated for functional alterations. A novel disease gene for hypertrophic cardiomyopathy was identified, which altered methylation status of several specific loci in genome DNA. Analysis of transgenic mice specifically expressing human M21 in the heart demonstrated that high expression of M21 lead to cardiomyocytes hypertrophy with myofibrillar disarrays and later development of systolic dysfunction resembling to dilated phase hypertrophic cardiomyopathy, while low expression of M21 did not. Gene expression study revealed that expression of cardiac remodeling genes were altered even in the hearts from mice with low expressing M21, while MAP kinase and TGFb pathways were specifically changed only in the hearts from mice with high expression of M21.

Academic Significance and Societal Importance of the Research Achievements

本研究では、遺伝性心筋症・遺伝性不整脈について、既知の原因遺伝子の変異を網羅的に検索するシステムを構築し、その有用性を示した。また、新たに見出した多数の病因変異の機能異常を解明した。とりわけ、RBM20変異による拡張型心筋症の病態形成機序やカルシウム感受性異常が肥大型心筋症の病態形成に至る機序を解明した。さらに、新規の原因遺伝子を複数同定した。これらの知見は、遺伝性心疾患の診断や病態解明に供するのみならず、一般の心不全・不整脈の病態解明ひいては治療法開発にも繋がる。

Research Products

• [Int'l Joint Research] Columbia University/Indiana University/University of California(米国)
• [Int'l Joint Research] Columbia University(米国)
• [Int'l Joint Research] Inst Mol Biotech Austrian Acad Sci(オーストリア)
• [Journal Article] MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages (2019)
  • Author(s): An J, Naruse TK, Hinohara K, Soejima Y, Sawabe M, Nakagawa Y, Kuwahara K, Kimura A
  • Journal Title: Journal of Molecular Cellular Cardiology Volume: 未定
  • NAID: 130007811832
  • Peer Reviewed
• [Journal Article] Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance (2018)
  • Author(s): Arimura Takuro、Muchir Antoine、Kuwahara Masayoshi、Morimoto Sachio、Ishikawa Taisuke、Du Cheng-Kun、Zhan Dong-Yun、Nakao Shu、Machida Noboru、Tanaka Ryo、Yamane Yoshihisa、Hayashi Takeharu、Kimura Akinori
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: epub Issue: 6 Pages: H1192-H1202
  • DOI: 10.1152/ajpheart.00696.2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization (2018)
  • Author(s): Rie Murayama, Mariko Kimura-Asami, Marina Togo-Ohno, Yumiko Yamasaki-Kato, Taeko K. Naruse, Takeshi Yamamoto, Takeharu Hayashi, Tomohiko Ai, Katherine G. Spoonamore, Richard J. Kovacs, Matteo Vatta, Mai Iizuka, Masumi Saito, Shotaro Wani, Yuichi Hiraoka, Akinori Kimura & Hidehito Kuroyanagi
  • Journal Title: Scientific Reports Volume: 印刷中 Issue: 1 Pages: 8970-8983
  • DOI: 10.1038/s41598-018-26624-w
  • NAID: 120007031665
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy (2018)
  • Author(s): Hayashi Takeharu、Tanimoto Kousuke、Hirayama-Yamada Kayoko、Tsuda Etsuko、Ayusawa Mamoru、Nunoda Shinichi、Hosaki Akira、Kimura Akinori
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 9 Pages: 989-996
  • DOI: 10.1038/s10038-018-0479-y
  • Peer Reviewed
• [Journal Article] Clinical and genetic backgrounds of hypertrophic cardiomyopathy with mid-ventricular obstruction (2018)
  • Author(s): Inagaki Natsuko、Hayashi Takeharu、Takei Yasuyoshi、Tanimoto Kousuke、Chikamori Taishiro、Kimura Akinori
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 12 Pages: 1273-1276
  • DOI: 10.1038/s10038-018-0509-9
  • Peer Reviewed
• [Journal Article] Alternative splicing regulator RBM20 in cardiomyopathy (2018)
  • Author(s): Watanabe T, Kimura A, Kuroyanagi H
  • Journal Title: Frontiers in Molecular Biosciences Volume: 5 Issue: 2 Pages: 105-105
  • DOI: 10.1016/j.micinf.2018.10.001
  • NAID: 120007150215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Barth syndrome associated with triple mutation. (2018)
  • Author(s): Tsujii N, Nishikubo T. et al
  • Journal Title: Pediatr Int. Volume: 60 Issue: 4 Pages: 385-7
  • DOI: 10.1111/ped.13517
  • Peer Reviewed
• [Journal Article] The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function (2018)
  • Author(s): Yamaguchi Tomokazu et al
  • Journal Title: Science Signaling Volume: 11 Issue: 516 Pages: 3638-3638
  • DOI: 10.1126/scisignal.aan3638
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage (2017)
  • Author(s): Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, Yamaguchi T, Kimura A, Fukamizu A, Penninger JM, Reversade B, Ito H, Imai Y, Kuba K
  • Journal Title: Cardiovasc Res Volume: 113(7) Issue: 7 Pages: 760-769
  • DOI: 10.1093/cvr/cvx061
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] MKL1 expressed in macrophages contributes to the development of murine colitis. (2017)
  • Author(s): Jianbo An, Takashi Nagaishi, Taro Watabe, Taeko K. Naruse, Mamoru Watanabe, Akinori Kimura
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 13650-13650
  • DOI: 10.1038/s41598-017-13629-0
  • Peer Reviewed / Open Access
• [Journal Article] Familial hypertrophic obstructive cardiomyopathy with the GLA E66Q mutation and Zebra body (2016)
  • Author(s): Oikawa M, Sakamoto N, Kobayashi A, Suzuki A, Yoshihisa A. Yamaki T, Nakazato K, Suzuki H, Saitoh S, Kiko Y, Nakano H, Hayashi T, Kimura A, Takeishi Y
  • Journal Title: BMC Cardiovasc Disord. Volume: 16 Issue: 1 Pages: 83-83
  • DOI: 10.1186/s12872-016-0262-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hypertrophic Cardiomyopathy Accompanied by Spinocerebellar Atrophy With a Novel Mutation in Troponin I Gene (2016)
  • Author(s): Kawai H, Morimoto S, Takakuwa Y, Ueda A, Inada K, Sarai M, Arimura T, Mutoh T, Kimura A, Ozaki Y
  • Journal Title: International Heart Journal Volume: 57 Issue: 4 Pages: 507-510
  • DOI: 10.1536/ihj.15-444
  • NAID: 130006895905
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 拡張型心筋症における遺伝子異常と分子病態 (2017)
  • Author(s): 木村 彰方
  • Organizer: 第３回 日本心筋症研究会
  • Invited
• [Presentation] Genetic basis and molecular pathogenesis of primary cardiomyopathy (2017)
  • Author(s): 木村 彰方
  • Organizer: 第21 回 日本心不全学会学術集会
  • Invited
• [Presentation] αトロポミオシン1(TPM1) 遺伝子にミスセンス変異を伴った若年性肥大型心筋症の一 家系 (2016)
  • Author(s): 渡邊俊介、義久精臣、安齋文弥、菅野優紀、上岡正志、鈴木聡、及川雅啓、小林淳、國井浩行、林丈晴、木 村彰方、竹石恭知
  • Organizer: 第２回日本心筋症研究会
  • Place of Presentation: まつもと市民芸術館（長野県、松本市）
  • Year and Date: 2016-05-14
• [Presentation] 若年、小児発症の肥大型及び拘束型心筋症の原因遺伝子解析 (2016)
  • Author(s): 林 丈晴、谷本幸介、木村彰方
  • Organizer: 第２回日本心筋症研究会
  • Place of Presentation: まつもと市民芸術館（長野県、松本市）
  • Year and Date: 2016-05-14