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Genetic dissection of rare MODY by multidisciplinary functional genomics

Research Project

Project/Area Number 18H02779
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionGifu University

Principal Investigator

HORIKAWA YUKIO  岐阜大学, 医学部附属病院, 准教授 (10323370)

Co-Investigator(Kenkyū-buntansha) 塩谷 真由美  岐阜大学, 医学部附属病院, 講師 (10293565)
飯塚 勝美  岐阜大学, 医学部附属病院, 講師 (40431712)
細道 一善  金沢大学, 医学系, 准教授 (50420948)
矢部 大介  岐阜大学, 大学院医学系研究科, 教授 (60378643)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
KeywordsMODY / 原因遺伝子 / HNF / 単一遺伝子疾患 / 多因子疾患 / インスリン分泌 / 次世代シークエンサー / コピー数変異 / エンハンサー / エクソーム / in situ hybridization / 機能ゲノミクス / 遺伝子診断 / 候補遺伝子パネル / インスリン分泌不全 / 細胞骨格分子 / トランスクリプトーム / レギュローム
Outline of Final Research Achievements

The cytoskeletal molecule MYO5A was identified as a promising novel MODY candidate gene by combining linkage analysis and exosome by NGS with special reference to the islet functional network. On the other hand, the type 2 diabetes susceptibility gene, calpain 10 was subjected to analysis using an ultrasensitive mass spectrometer, and the microtubule-binding protein (MAP1B) was identified as a target substrate. Interestingly, MAP1B and MYO5A are known to be important partners in the cytoskeleton and may be coordinated in insulin secretion. In addition, a novel regulatory mechanism of glucokinase was found to be mediated by ubiquitination by cereblon, and the mechanism of low insulin secretion by arginine in MODY2 was elucidated.

Academic Significance and Societal Importance of the Research Achievements

MODY1-6 遺伝子にコードされる一連のHNF転写因子ネットワークの知見は、インスリン分泌調節のみならず、膵島の発生・分化のプログラムの理解に大きく貢献した。新規MODY候補遺伝子MYO5AとMAP1Bの相互作用やグルコキナーゼ(MODY2)のアルギニンを介した新規制御機構など膵島における新たな機能プログラムの解明は、新規インスリン分泌促進薬の開発研究やその周辺因子による膵島再生や新生による糖尿病根治的治療の開発研究にも発展しうる。さらに本研究成果は、メンデル遺伝のみならず、多因子疾患である2型糖尿病にも貢献する一方、本戦略成果は他の遺伝性の希少疾患の解析モデルにもなるであろう。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report

Research Products

(42 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (16 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 14 results,  Open Access: 9 results) Presentation (13 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results) Book (10 results) Remarks (2 results)

  • [Int'l Joint Research] University of Copenhagen(デンマーク)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] A novel RFX6 heterozygous mutation (p.R652X) in maturity‐onset diabetes mellitus: A case report2021

    • Author(s)
      Imaki Sakiho、Iizuka Katsumi、Horikawa Yukio、Yasuda Megumi、Kubota Sodai、Kato Takehiro、Liu Yanyan、Takao Ken、Mizuno Masami、Hirota Takuo、Suwa Tetsuya、Hosomichi Kazuyoshi、Tajima Atsushi、Fujiwara Yuuka、Yamazaki Yuji、Kuwata Hitoshi、Seino Yutaka、Yabe Daisuke
    • Journal Title

      Journal of diabetes investigation

      Volume: in press Pages: 1914-1918

    • DOI

      10.1111/jdi.13545

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of ChREBP deficiency on adrenal lipogenesis and steroidogenesis2021

    • Author(s)
      Takao Ken、Iizuka Katsumi、Liu Yanyan、Sakurai Teruaki、Kubota Sodai、Kubota-Okamoto Saki、Imaizumi Toshinori、Takahashi Yoshihiro、Rakhat Yermek、Komori Satoko、Hirose Tokuyuki、Nonomura Kenta、Kato Takehiro、Mizuno Masami、Suwa Tetsuya、Horikawa Yukio、Sone Masakatsu、Yabe Daisuke
    • Journal Title

      J. Endocrinol.

      Volume: 248 Pages: 317-324

    • DOI

      10.1530/joe-20-0442

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells2020

    • Author(s)
      Cho J, Horikawa Y, Enya M, Takeda J, Imai Y, Imai Y, Handa H, and Imai T
    • Journal Title

      Commun Biol

      Volume: 3 Pages: 497-497

    • DOI

      10.1038/s42003-020-01226-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of hypertriglyceridemia in dyslipidemia-induced impaired glucose tolerance and sex differences in dietary features associated with hypertriglyceridemia among the Japanese population: The Gifu Diabetes Study.2020

    • Author(s)
      Nonoyama Y, Yamamoto M, Oba S, Horikawa Y, Nagata C, Yabe D, and Takeda J; Gifu Diabetes Study Group.
    • Journal Title

      J Diabetes Investig

      Volume: -

    • DOI

      10.1111/jdi.13398

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Alcohol-induced impaired insulin secretion in a Japanese population: Five-year follow-up in the Gifu Diabetes Study2020

    • Author(s)
      Ueda N, Yamamoto M, Nakamura M, Motooka Y, Nakayama Y, Nonoyama,Y, Oba S, Horikawa Y, Nagata C, and Yabe D; Gifu Diabetes Study Group
    • Journal Title

      J Diabetes Investig

      Volume: 11 Pages: 1207-1214

    • DOI

      10.1111/jdi.13260

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A case of MODY5-like manifestations without mutations or deletions in coding and minimal promoter regions of the HNF1B gene.2020

    • Author(s)
      Kuwabara-Ohmura y, Iizuka K, Liu Y, Takao K, Nonomura K, T Kato, Mizuno M, Hosomichi K, Miyazaki T, Horikawa Y, Yabe D
    • Journal Title

      Endocr J

      Volume: -

    • NAID

      130007910088

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Periodontal disease may be associated with the occurrence of diabetic retinopathy: A subgroup analysis of the survey of the Diabetes Coordination Notebook in Gifu2020

    • Author(s)
      Horikawa Y, Suzuki A, Enya M, Hashimoto K, Nishida S, Kobayashi R, Ohashi T, Yamazaki F, Totani R, Kobayashi H, Yamamoto M, Itoh Y and Takeda J
    • Journal Title

      Exp Clin Endocrinol Diabetes

      Volume: -

    • DOI

      10.1055/a-0879-1890

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Genetic dissection and clinical features of MODY6 (NEUROD1-MODY)2019

    • Author(s)
      Horikawa Y and Enya M.
    • Journal Title

      Curr Diab Rep

      Volume: 19 Pages: 12-12

    • DOI

      10.1007/s11892-019-1130-9

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] KLF11 variant in a family clinically diagnosed with early childhood‐onset type 1B diabetes2019

    • Author(s)
      Ushijima Kikumi、Narumi Satoshi、Ogata Tsutomu、Yokota Ichiro、Sugihara Shigetaka、Kaname Tadashi、Horikawa Yukio、Matsubara Yoichi、Fukami Maki、Kawamura Tomoyuki、The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes
    • Journal Title

      Pediatr Diabetes

      Volume: 20 Pages: 712-719

    • DOI

      10.1111/pedi.12868

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of <i>HNF1B</i> based on 17q12 microdeletion2019

    • Author(s)
      Omura Yoshiyuki、Yagi Kunimasa、Honoki Hisae、Iwata Minoru、Enkaku Asako、Takikawa Akiko、Kuwano Takahide、Watanabe Yoshiyuki、Nishimura Ayumi、Liu Jianhui、Chujo Daisuke、Fujisaka Shiho、Enya Mayumi、Horikawa Yukio、Tobe Kazuyuki
    • Journal Title

      Endocr J

      Volume: 66 Issue: 12 Pages: 1113-1116

    • DOI

      10.1507/endocrj.ej19-0020

      10.1507/endocrj.EJ19-0020

    • NAID

      130007772410

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Knowledge of diabetes and its determinants: a cross-sectional study among adults in a Japanese community.2019

    • Author(s)
      Oba S, Yamamoto M, Horikawa Y, Suzuki E, Nagata C, Takeda J, and the Gifu Diabetes Study Group
    • Journal Title

      BMJ Open

      Volume: 9

    • DOI

      10.1136/bmjopen-2018-024556

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MODY遺伝情報と臨床的知見を糖尿病日常臨床にどう活かすか?2019

    • Author(s)
      堀川幸男
    • Journal Title

      科学評論社

      Volume: 48 Pages: 181-187

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B2018

    • Author(s)
      Hatta Tomohisa、Iemura Shun-ichiro、Ohishi Tomokazu、Nakayama Hiroshi、Seimiya Hiroyuki、Yasuda Takao、Iizuka Katsumi、Fukuda Mitsunori、Takeda Jun、Natsume Tohru、Horikawa Yukio
    • Journal Title

      Sci. Rep.

      Volume: 8 Pages: 16756-16756

    • DOI

      10.1038/s41598-018-35204-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY2018

    • Author(s)
      Horikawa Y, Hosomichi K, Ishiura H, Suzuki Y, Tsuji S, Inoue I, Takeda J
    • Journal Title

      Journal of human genetics

      Volume: 印刷中 Pages: 821-829

    • DOI

      10.1038/s10038-018-0449-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Maturity-onset diabetes of the young (MODY) as a model for elucidating the multifactorial origin of type 2 diabetes mellitus.2018

    • Author(s)
      Horikawa Y.
    • Journal Title

      J Diabetes Investig

      Volume: 9 Pages: 704-712

    • DOI

      10.1111/jdi.12812

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 若年発症成人型糖尿病(MODY) -多因子型コモン2型糖尿病のモデル疾患として2018

    • Author(s)
      堀川幸男、塩谷真由美
    • Journal Title

      プラクティス

      Volume: 35 Pages: 378-383

    • Related Report
      2018 Annual Research Report
  • [Presentation] Whole-exome sequencing in a family with multiple cases of early-onset diabetes reveals a candidate causative mutation in the PTF1A gene.2020

    • Author(s)
      Tanaka D, Okamoto S, Liu Y, Iizuka K, Hamamoto Y, Horikawa Y, Yabe D, Inagaki N.
    • Organizer
      56th Annual Meeting of the European Association for the Study of Diabetes
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Exome Sequencing in a Family with Multiple Cases of Early-Onset Diabetes Reveals a Candidate Causative Mutation in the PTF1A Gene.2020

    • Author(s)
      Tanaka D, Okamoto S, Liu Y, Iizuka K, Hamamoto Y, Horikawa Y, Yabe D, Inagaki N.
    • Organizer
      80th Scientific Sessions, American Diabetes Association
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] RFX6 遺伝子変異を同定した若年発症糖尿病の1 例2020

    • Author(s)
      今木咲歩、飯塚勝美、安田愛、窪田創大、加藤丈博、細道一善、田島敦、藤原結花、桑田仁司、堀川幸男、矢部大介
    • Organizer
      第94回日本糖尿病学会中部地方会 (会長 堀川幸男)
    • Related Report
      2020 Annual Research Report
  • [Presentation] High-Sucrose Diet Causes Increased Hepatic Histone Acetylation Due to Increased Bacterial Acetate Production and Reduced Lipogenesis in ChREPB-Deficient Mice.2020

    • Author(s)
      Iizuka K, Takao K, Liu Y, Nonomura K, Kato T, Mizuno M, Horikawa Y, Yabe D.
    • Organizer
      80th Scientific Sessions, American Diabetes Association.
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] SGLT2阻害薬、GLP-1受容体作動薬の治療効果予測因子の検討2020

    • Author(s)
      酒井 麻有、飯塚 勝美、石原 拓磨、鷹尾 賢、加藤 丈博、野々村 健太、劉 彦言、水野 正巳、堀川 幸男、矢部大介
    • Organizer
      第63回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] メガゲノミクスによる糖尿病遺伝素因の同定(シンポジウム)2019

    • Author(s)
      細道一善、堀川幸男
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 新規インスリン遺伝子変異を同定しMODY10と考えられた1家系2019

    • Author(s)
      塩谷 真由美 金子 至寿佳 矢部 大介 堀川 幸男
    • Organizer
      第53回日本小児内分泌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 日本人初MODY4(PDX1-MODY)の1症例についての報告2019

    • Author(s)
      塩谷 真由美、吉治智志、阿部 恵、濱崎 暁洋、細道 一善、矢部 大介、堀川 幸男
    • Organizer
      第64回日本人類遺伝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] FGF21誘導におけるChREBPとPPARαの協調作用2019

    • Author(s)
      鷹尾 賢、飯塚勝美、加藤丈博、堀川幸男
    • Organizer
      第92回日本内分泌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ChREBP欠失マウスではSGLT2阻害薬による血糖低下作用が現弱する2019

    • Author(s)
      加藤丈博、飯塚勝美、鷹尾 賢、堀川幸男
    • Organizer
      第92回日本内分泌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 遺伝子異常と糖尿病2018

    • Author(s)
      堀川幸男 (教育講演)
    • Organizer
      第61回日本糖尿病学会年次学術集会.
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 単一遺伝子異常による糖尿病(MODY)表現型への子宮内環境の影響に関する検討2018

    • Author(s)
      塩谷真由美、堀川幸男, 水野正巳, 橋本健一,廣田卓男, 諏訪哲也, 武田 純
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 若年発症糖尿病(MODY)における片親起源効果についての包括的検討2018

    • Author(s)
      塩谷真由美、酒井麻有、野々村健太、鷹尾 賢、加藤丈博、水野正巳、橋本健一、廣田卓男、飯塚勝美、諏訪哲也、堀川幸男
    • Organizer
      第34回日本糖尿病妊娠学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Book] 臨床遺伝専門医テキストシリーズ(成人領域)遺伝子異常による代謝疾患―糖尿病.2021

    • Author(s)
      堀川幸男
    • Total Pages
      8
    • Publisher
      診断と治療社
    • Related Report
      2020 Annual Research Report
  • [Book] 月刊糖尿病. 堀川幸男(編集) 遺伝子異常と糖尿病  MODY1-62020

    • Author(s)
      塩谷真由美、堀川幸男
    • Total Pages
      8
    • Publisher
      医学出版
    • ISBN
      9784287821237
    • Related Report
      2020 Annual Research Report
  • [Book] 岐阜県医師会医学雑誌 岐阜県下における「糖尿病連携手帳」の実態調査.2020

    • Author(s)
      堀川幸男
    • Total Pages
      5
    • Publisher
      岐阜県医師会
    • Related Report
      2020 Annual Research Report
  • [Book] DM Ensemble 糖尿病性腎症重症化予防プログラムと糖尿病連携手帳の活用.2020

    • Author(s)
      矢部大介、加藤丈博、堀川幸男
    • Total Pages
      6
    • Publisher
      日本糖尿病協会
    • Related Report
      2020 Annual Research Report
  • [Book] 特集 糖尿病診療update : 最新の診断と治療 糖尿病に関する教育と支援2020

    • Author(s)
      酒井 麻有、窪田 創大、加藤 丈博、堀川 幸男、矢部 大介
    • Total Pages
      6
    • Publisher
      日本臨床
    • Related Report
      2020 Annual Research Report
  • [Book] 内分泌症候群(第3版)若年発症糖尿病(MODY)の遺伝素因と臨床病態について2019

    • Author(s)
      塩谷真由美、堀川幸男
    • Total Pages
      7
    • Publisher
      日本臨床社
    • Related Report
      2019 Annual Research Report
  • [Book] 糖尿病 単一遺伝子異常による糖尿病-MODY2019

    • Author(s)
      堀川幸男
    • Total Pages
      3
    • Publisher
      日本糖尿病学会
    • Related Report
      2019 Annual Research Report
  • [Book] 糖尿病・内分泌代謝科 MODY遺伝情報と臨床的知見を糖尿病日常臨床にどう活かすか? 1000万通りの糖尿病個別化医療に向けた遺伝情報の活用のしかた2019

    • Author(s)
      堀川幸男
    • Total Pages
      7
    • Publisher
      科学評論社
    • Related Report
      2019 Annual Research Report
  • [Book] 内分泌症候群(第3版)2019

    • Author(s)
      塩谷真由美、堀川幸男
    • Total Pages
      642
    • Publisher
      日本臨床
    • Related Report
      2018 Annual Research Report
  • [Book] 内分泌代謝専門医ガイドブック2018

    • Author(s)
      堀川幸男、武田 純
    • Total Pages
      763
    • Publisher
      診断と治療社
    • ISBN
      9784787822925
    • Related Report
      2018 Annual Research Report
  • [Remarks] 岐阜大学大学院医学系研究科内分泌代謝内科学

    • URL

      http://www.med.gifu-u.ac.jp/diabetes/achievement/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 岐阜大学大学院医学系研究科内分泌代謝病態学 糖尿病代謝内科・免疫内分泌内科ホームページ

    • URL

      http://www.med.gifu-u.ac.jp/diabetes/

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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