Clarification of molecular basis of type 1 diabetes using novel technologies

• Project/Area Number: 16K15491
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Fukami Maki 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 部長 (40265872)
• Co-Investigator(Kenkyū-buntansha): 綾部 匡之 国立研究開発法人国立成育医療研究センター, 生体防御系内科部, 研究員 (80566555)
• Research Collaborator: OKUNO MISAKO ; USHIJIMA KIKUMI
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 遺伝子 / 疾患 / 感受性 / 糖尿病 / 疾患感受性

Outline of Final Research Achievements

Type 1 diabetes (T1D) is a multifactorial disorder, whose genetic basis is only partly understood. Here, we performed systematic molecular analysis for Japanese patients with this condition. We employed next generation sequencing and other new technologies. As a result, we identified novel T1D -associated genes such as PTPN2 and CD101. We also clarified clinical significance of rare variants in KLF11, RFX6, and other genes as the genetic causes of T1D. Furthermore, we found that a cis-regulatory haplotype at 17q12-q21 plays a role in the early-onset type 1 diabetes. These findings expand the current understanding of the etiology of type 1 diabetes.

Academic Significance and Societal Importance of the Research Achievements

1型糖尿病は、生涯にわたる治療を必要とし、また多彩な合併症を招きうる難治性疾患である。本症の発症原因には未解明の点が多い。本研究では、日本人患者における既知遺伝子変異の特徴を明らかとし、また、1型糖尿病に関与すると推測される新たな遺伝子変異を明らかとした。これらの知見は、人種特異的な1型糖尿病の発症メカニズムの解明につながる。

Research Products

• [Journal Article] A heterozygous protein‐truncating RFX 6 variant in a family with childhood‐onset, pregnancy‐associated and adult‐onset diabetes (2019)
  • Author(s): Akiba K.、Ushijima K.、Fukami M.、Hasegawa Y.
  • Journal Title: Diabetic Medicine Volume: 未定 Issue: 10 Pages: 1772-1776
  • DOI: 10.1111/dme.13970
  • Peer Reviewed / Open Access
• [Journal Article] The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes. KLF11 (MODY7) variant in a family clinically diagnosed with early childhood-onset type 1B diabetes (2019)
  • Author(s): Ushijima K, Narumi S, Ogata T, Yokota I, Sugihara S, Kaname T, Horiwaka Y, Matsubara Y, Fukami M, Kawamura T
  • Journal Title: Pediatric Diabetes Volume: 未定
  • Peer Reviewed
• [Journal Article] Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes (2018)
  • Author(s): Okuno M.、Ayabe T.、Yokota I.、Musha I.、Shiga K.、Kikuchi T.、Kikuchi N.、Ohtake A.、Nakamura A.、Nakabayashi K.、Okamura K.、Momozawa Y.、Kubo M.、Suzuki J.、Urakami T.、Kawamura T.、Amemiya S.、Ogata T.、Sugihara S.、Fukami M.、the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes
  • Journal Title: Diabetic Medicine Volume: 35 Issue: 3 Pages: 376-380
  • DOI: 10.1111/dme.13566
  • Peer Reviewed
• [Journal Article] Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes (2017)
  • Author(s): Ushijima K, Fukami M, Ayabe T, Narumi S, Okuno M, Nakamura A, Takahashi T, Ihara K, Ohkubo K, Tachikawa E, Nakayama S, Arai J, Kikuchi N, Kikuchi T, Kawamura T, Urakami T, Hata K, Nakabayashi K, Matsubara Y, Amemiya S, Ogata T, Yokota I, Sugihara S
  • Journal Title: Pediatric Diabetes Volume: 19 Issue: 2 Pages: 243-250
  • DOI: 10.1111/pedi.12544
  • Peer Reviewed
• [Journal Article] Nucleotide substitutions in CD101, the human homolog of a diabetes susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes. (2017)
  • Author(s): Okuno M, Kasahara Y, Onodera M, Takubo N, Okajima M, Suga S, Watanabe N, Suzuki J, Ayabe T, Urakami T, Kawamura T, Kikuchi N, Yokota I, Kikuchi T, Amemiya S, Nakabayashi K, Hayashi K, Hata K, Matsubara Y, Ogata T, Fukami M, Sugihara S
  • Journal Title: J Diabetes Investig. Volume: 印刷中 Issue: 3 Pages: 286-294
  • DOI: 10.1111/jdi.12586
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21. (2016)
  • Author(s): Ayabe T, Fukami M, et al.
  • Journal Title: Diabet Med. Volume: 33 Issue: 12 Pages: 1717-1722
  • DOI: 10.1111/dme.13175
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 次世代シークエンサーを用いた1型糖尿病感受性因子の探索 (2018)
  • Author(s): 深見真紀
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] 1B型糖尿病発症における単一遺伝子変異の寄与の解明 (2017)
  • Author(s): 牛嶋規久美, 深見真紀, 綾部匡之, 奥野美佐子, 鳴海覚志, 緒方勤, 菊池信行, 菊池透, 川村智行, 浦上達彦, 横田一郎, 雨宮伸, 杉原茂孝
  • Organizer: 第90回日本内分泌学会学術集会
• [Presentation] 若年発症1B型糖尿病家系で同定した新規KLF11変異について-KLF11変異の表現型スペクトラムの拡張 (2017)
  • Author(s): 牛嶋規久美, 深見真紀, 鳴海覚志, 緒方勤, 浦上達彦, 横田一郎, 菊池信行, 菊池透, 雨宮伸, 杉原茂孝, 川村智行
  • Organizer: 第51回日本小児内分泌学会学術集会
• [Presentation] Nucleotide substitutions in CD101, the human homolog of diabetes mellitus susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes mellitus (2016)
  • Author(s): Okuno M, Kasahara Y, Takubo N, Okajima M, Suga S, Suzuki J, Ayabe T, Urakami T, Kawamura T, Kikuchi N, Yokota I, Kikuchi T, Amemiya S, Ogata T, Fukami M, Sugihara S
  • Organizer: The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society
  • Place of Presentation: 東京
  • Year and Date: 2016-11-19
  • Int'l Joint Research
• [Presentation] Next-generation sequencing-based comprehensive mutation screening in 89 Japanese children clinically diagnosed with type 1B diabetes (2016)
  • Author(s): Ushijima K, Fukami M, Ayabe T, Okuno M, Narumi S, Ogata T, Kikuchi N, Kikuchi T, Kawamura T, Urakami T, Yokota I, Amemiya S, Sugihara S
  • Organizer: The 9th Biennial Scientific Meeting of the Asia Pacific Paediatric Endocrine Society
  • Place of Presentation: 東京
  • Year and Date: 2016-11-18
  • Int'l Joint Research
• [Presentation] ucleotide substitutions in CD101, the human homolog of diabetes mellitus susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes mellitus. (2016)
  • Author(s): Okuno M, Kasahara Y, Takubo N, Okajima M, Suga S, Suzuki J, Ayabe T, Urakami T, Kawamura T, Kikuchi N, Yokota I, Kikuchi T, Amemiya S, Ogata T, Fukami M, Sugihara S.
  • Organizer: 42th Annual Conference of the International Society for Pediatrics and Adolescent Diabetes
  • Place of Presentation: Spain
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Remarks] 国立研究開発法人国立成育医療研究センター 分子内分泌研究部
  • URL: http://nrichd.ncchd.go.jp/endocrinology/
• [Remarks] 研究開発法人国立成育医療研究センター分子内分泌研究部
  • URL: https://www.ncchd.go.jp/scholar/research/section/endocrinology/index.html
• [Remarks] 研究開発法人国立成育医療研究センター
  • URL: https://www.ncchd.go.jp/index.html
• [Remarks] 研究開発法人国立成育医療研究センター分子内分泌研究部
  • URL: http://nrichd.ncchd.go.jp/endocrinology/