Study on disease modifiers relating to TGF-beta signal pathway for aortic diseases

• Project/Area Number: 16K09486
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: The University of Tokyo (2018); Tokyo University of Technology (2016-2017)
• Principal Investigator: MORISAKI TAKAYUKI 東京大学, 医科学研究所, 特任教授 (30174410)
• Co-Investigator(Kenkyū-buntansha): 森崎 裕子 公益財団法人日本心臓血圧研究振興会(臨床研究施設・研究部門), 臨床遺伝科医局, 医長 (40311451)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 大動脈瘤 / 大動脈解離 / 遺伝性動脈疾患 / TGF-βシグナル / 病態修飾因子 / 遺伝子バリアント / 循環器 / 遺伝子 / 遺伝学 / 発現制御 / 内科

Outline of Final Research Achievements

In this study, we performed genetic analysis by the next generation sequencer on patients with young aortic diseases based on our previous study on more than 1,500 patients and relatives. Data of these genetic data and clinical information revealed new genetic variants as pathogenic and modifying ones. Also some variants were found to be pathogenic variants in patients with specific clinical features. Based on our results with other results by foreign collaborating researchers, we are establishing clinically relevant criteria to determine pathogenic variants in genes especially relating to TGF-beta signaling pathway. These results will help for better and faster diagnosis and intervention of these aortic diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究により、遺伝性大動脈疾患について、病因や病型の同定に資する遺伝子解析について、効率よく安価に実施出来る手法を確立し、その有用性を確認することができた。国内随一の検討結果であり、手法の確立と普及により、若年性（遺伝性）大動脈疾患の適切な診断と治療につながる検査手法を確立し、さらに病態修飾あるいは病型分類に関わる遺伝子バリアントの評価法の確立にもつながった。成果は国外の研究協力者との間の検討により、日本人患者の特徴の把握にもつながっており、日本の若年性大動脈疾患の医療に貢献し意義深い。

Research Products

• [Journal Article] Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations (2018)
  • Author(s): Regalado ES、Montalcino Aortic Consortium、Mellor-Crummey L et al
  • Journal Title: Genetics in Medicine Volume: 20 Issue: 10 Pages: 1206-1215
  • DOI: 10.1038/gim.2017.245
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3 (2018)
  • Author(s): Schepers Dorien、Tortora Giada、Morisaki Takayuki et al.
  • Journal Title: Human Mutation Volume: 39 Issue: 5 Pages: 621-634
  • DOI: 10.1002/humu.23407
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Assessing the Accuracy of Variant Detection in Cost-Effective Gene Panel Testing by Next-Generation Sequencing. (2018)
  • Author(s): Fujiki R, Ikeda M, Yoshida A, Akiko M, Yao Y, Nishimura M, Matsushita K, Ichikawa T, Tanaka T, Morisaki H, Morisaki T, Ohara O.
  • Journal Title: J Mol Diagn. Volume: 96 Issue: 5 Pages: 572-582
  • DOI: 10.1016/j.jmoldx.2018.04.004
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection (2018)
  • Author(s): Renard Marjolijn、Francis Catherine、Ghosh Rajarshi、et al
  • Journal Title: Journal of the American College of Cardiology Volume: 72 Issue: 6 Pages: 605-615
  • DOI: 10.1016/j.jacc.2018.04.089
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cited4 is related to cardiogenic induction and maintenance of proliferation capacity of embryonic stem cell-derived cardiomyocytes during in vitro cardiogenesis (2017)
  • Author(s): Miake Junichiro、Notsu Tomomi、Higaki Katsumi、Hidaka Kyoko、Morisaki Takayuki、Yamamoto Kazuhiro、Hisatome Ichiro
  • Journal Title: PLOS ONE Volume: 12 Issue: 8 Pages: e0183225-e0183225
  • DOI: 10.1371/journal.pone.0183225
  • Peer Reviewed / Open Access
• [Journal Article] Vestigial-like 2 contributes to normal muscle fiber type distribution in mice (2017)
  • Author(s): Honda Masahiko、Hidaka Kyoko、Fukada So-ichiro、Sugawa Ryo、Shirai Manabu、Ikawa Masahito、Morisaki Takayuki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 734-740
  • DOI: 10.1038/s41598-017-07149-0
  • NAID: 120006957431
  • Peer Reviewed / Open Access
• [Journal Article] Role of AMPD2 in impaired glucose tolerance induced by high fructose diet (2017)
  • Author(s): Hudoyo Athanasius Wrin、Hirase Tetsuaki、Tandelillin Andreas、Honda Masahiko、Shirai Manabu、Cheng Jidong、Morisaki Hiroko、Morisaki Takayuki
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 13 Pages: 23-29
  • DOI: 10.1016/j.ymgmr.2017.07.006
  • Peer Reviewed
• [Journal Article] Clinical outcomes of aortic repair in young adult patients with ACTA2 mutations (2017)
  • Author(s): Seike Yoshimasa、Minatoya Kenji、Sasaki Hiroaki、Tanaka Hiroshi、Itonaga Tatsuya、Inoue Yosuke、Morisaki Hiroko、Morisaki Takayuki、Ishibashi-Ueda Hatsue、Kobayashi Junjiro
  • Journal Title: General Thoracic and Cardiovascular Surgery Volume: 65 Issue: 12 Pages: 686-691
  • DOI: 10.1007/s11748-017-0810-0
  • Peer Reviewed
• [Journal Article] Impact of connective tissue disease on the surgical outcomes of aortic dissection in patients with cystic medial necrosis (2017)
  • Author(s): Fujiyoshi Toshiki、Minatoya Kenji、Ikeda Yoshihiko、Ishibashi-Ueda Hatsue、Morisaki Takayuki、Morisaki Hiroko、Ogino Hitoshi
  • Journal Title: Journal of Cardiothoracic Surgery Volume: 12 Issue: 1 Pages: 97-97
  • DOI: 10.1186/s13019-017-0663-8
  • Peer Reviewed
• [Journal Article] Endovascular treatment of a dural arteriovenous fistula in a patient with Loeys-Dietz syndrome: A case report. (2017)
  • Author(s): Aoki R, Srivatanakul K, Osada T, Hotta K, Sorimachi T, Matsumae M, Morisaki H
  • Journal Title: Interv Neuroradiol Volume: 23 Issue: 2 Pages: 206-210
  • DOI: 10.1177/1591019916686054
  • Peer Reviewed
• [Journal Article] Moyamoya disease and artery tortuosity as rare phenotypes in a patient with an elastin mutation (2016)
  • Author(s): Ishiwata T, Tanabe N, Shigeta A, Yokota H, Tsushima K, Terada J, Sakao S, Morisaki H, Morisaki T, Tatsumi K:
  • Journal Title: Am J Med Genet A Volume: 170 Issue: 7 Pages: 1924-1927
  • DOI: 10.1002/ajmg.a.37662
  • Peer Reviewed
• [Journal Article] International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the Montalcino Aortic Consortium. (2016)
  • Author(s): Jondeau G, Ropers J, Regalado E, Braverman A, Evangelista A, Teixido G, De Backer J, Muiño-Mosquera L, Naudion S, Zordan C, Morisaki T, Morisaki H, Von Kodolitsch Y, Dupuis-Girod S, Morris SA, Jeremy R, Odent S, Adès LC, Bakshi M, Holman K, LeMaire S, Milleron O, Langeois M, Spentchian M, Aubart M, et al
  • Journal Title: Circ Cardiovasc Genet Volume: 9 Issue: 6 Pages: 548-558
  • DOI: 10.1161/circgenetics.116.001485
  • Peer Reviewed / Int'l Joint Research
• [Presentation] TMEPAI mutation causes MFS/LDS-like phenotypes in 2 Japanese families (2017)
  • Author(s): Hiroko Morisaki, Itaru Yamanaka, Takako Ohata, Tomoki Kosho, Keiko Wakui, Yoshimitsu Fukushima, Mitsuo Masuno, Kazuki Takahashi, Tetsuro Watabe, Takayuki Morisaki
  • Organizer: American Society of Human Genetics ASHG2017
  • Int'l Joint Research
• [Presentation] Genetic Aortopathy due to Gene Mutations Related and Not-related to TGF-β Signal Pathway in Japan (2016)
  • Author(s): Morisaki H, Watanabe T, Yoshida A, Ida K, Sasaki H, Minatoya K, Morisaki T
  • Organizer: American Society of Human Genetics (ASHG) 2016
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Familial Thoracic Aortic Aneurysms and Dissections (FTAAD) with ACTA2 Mutation in Japanese (2016)
  • Author(s): Morisaki T, Yoshida A, Watanabe T, Ida K, Sasaki H, Oda T, Tanaka H, Minatoya K, Morisaki H
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館（京都府、京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research