Investigation of novel causative mutations for young-onset diabetes using next-generation sequencing

• Project/Area Number: 18K08509
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kyoto University
• Principal Investigator: Tanaka Daisuke 京都大学, 医学研究科, 助教 (50582904)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 若年発症成人型糖尿病 / 次世代シーケンス / 糖尿病 / 家族性若年糖尿病

Outline of Final Research Achievements

The subjects of our study were patients diagnosed with antibody-negative diabetes before the age of 35 and their relatives. We selected 29 probands that were negative for known mutations in genes linked to maturity-onset diabetes of the young(MODY) and exome sequencing of their genome DNA was performed.
As a result, mutations in PTF1A gene(NC_000010.11:g.23192583C>T) and GATA6 gene (NC_000018.10:g.22171347A>T) were identified as candidates for novel causative mutations for young-onset diabetes.

Academic Significance and Societal Importance of the Research Achievements

1型糖尿病や2型糖尿病は多因子遺伝疾患であるが、単一遺伝子異常により発症する糖尿病が知られており、これまでに30以上の原因遺伝子が明らかとなっている。
一方、若年発症で、単一遺伝子異常による糖尿病が疑われるが、いまだ原因遺伝子変異が同定されない症例は多い。新規原因遺伝子変異の同定により、各症例の病態解明のみならず、糖尿病発症の分子機序に迫ることができると考える。

Research Products

• [Journal Article] A novel splice-site mutation of the HNF1B gene in a family with maturity onset diabetes of the young type 5 (MODY5) (2020)
  • Author(s): Fujita Yuki、Tanaka Daisuke、Tatsuoka Hisato、Matsubara Miho、Hyo Takanori、Hamamoto Yoshiyuki、Komiya Toshiyuki、Inagaki Nobuya、Seino Yutaka、Yamazaki Yuji
  • Journal Title: Endocrinology, Diabetes & Metabolism Case Reports Volume: 2020 Pages: 20-0092
  • DOI: 10.1530/edm-20-0092
  • Peer Reviewed / Open Access
• [Journal Article] Salient Ethical Issues in Genetic Analysis (2019)
  • Author(s): 田中 大祐、稲垣 暢也
  • Journal Title: Journal of the Japan Diabetes Society Volume: 62 Issue: 8 Pages: 474-476
  • DOI: 10.11213/tonyobyo.62.474
  • NAID: 130007696928
  • ISSN: 0021-437X, 1881-588X
  • Year and Date: 2019-08-30
• [Journal Article] Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion (2019)
  • Author(s): Liu Y, Harashima SI, Wang Y, Suzuki K, Tokumoto S, Usui R, Tatsuoka H, Tanaka D, Yabe D, Harada N, Hayashi Y, Inagaki N.
  • Journal Title: FASEB J. Volume: 33 Issue: 5 Pages: 6239-6253
  • DOI: 10.1096/fj.201801783rr
  • Peer Reviewed / Open Access
• [Journal Article] Reduction in Gastroesophageal Reflux Disease Symptoms Is Associated with <i>Miso</i> Soup Intake in a Population-Based Cross-Sectional Study: The Nagahama Study (2018)
  • Author(s): MANO Fumika、IKEDA Kaori、SATO Tosiya、NAKAYAMA Takeo、TANAKA Daisuke、JOO Erina、TAKAHASHI Yoshimitsu、KOSUGI Shinji、SEKINE Akihiro、TABARA Yasuharu、MATSUDA Fumihiko、INAGAKI Nobuya、Nagahama Study Group
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 64 Issue: 5 Pages: 367-373
  • DOI: 10.3177/jnsv.64.367
  • NAID: 130007501995
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2018-10-31
  • Peer Reviewed / Open Access
• [Journal Article] A Novel p.L145Q Mutation in the HNF1B Gene in a Case of Maturity-onset Diabetes of the Young Type 5 (MODY5) (2018)
  • Author(s): Kato T, Tanaka D, Muro S, Jambaljav B, Mori E, Yonemitsu S, Oki S, Inagaki N.
  • Journal Title: Internal Medicine Volume: 57 Issue: 14 Pages: 2035-2039
  • DOI: 10.2169/internalmedicine.9692-17
  • NAID: 130007404920
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-15
  • Peer Reviewed / Open Access
• [Journal Article] Dietary habits associated with reduced insulin resistance: The Nagahama study (2018)
  • Author(s): Ikeda Kaori、Sato Tosiya、Nakayama Takeo、Tanaka Daisuke、Nagashima Kazuaki、Mano Fumika、Joo Erina、Fujimoto Shimpei、Takahashi Yoshimitsu、Kosugi Shinji、Sekine Akihiro、Tabara Yasuharu、Matsuda Fumihiko、Inagaki Nobuya
  • Journal Title: Diabetes Research and Clinical Practice Volume: 141 Pages: 26-34
  • DOI: 10.1016/j.diabres.2018.04.006
  • Peer Reviewed / Open Access
• [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): DAISUKE TANAKA, SAKI OKAMOTO, YANYAN LIU, KATSUMI IIZUKA, YOSHIYUKI HAMAMOTO, YUKIO HORIKAWA, DAISUKE YABE, NOBUYA INAGAKI
  • Organizer: ADA 80th scientific sessions
  • 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): Daisuke Tanaka, Saki Okamoto, Yanyan Liu, Katsumi Iizuka, Yoshiyuki Hamamoto, Yukio Horikawa, Daisuke Yabe, and Nobuya Inagaki
  • Organizer: ADA the 80th Scientific Sessions
  • Int'l Joint Research