Analyses of the onset mechanism of Schaaf-Yang syndrome

• Project/Area Number: 18K15682
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya City University
• Principal Investigator: Yutaka Negishi 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (40798344)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Schaaf-Yang症候群 / MAGEL2 / CRISPR/Cas9 / モデルマウス / Prader-Willi症候群 / CRISPER/Cas9

Outline of Final Research Achievements

We generated genome-edited model that carried a truncating variant in Magel2 generated using the CRISPR/Cas9 system. The imprinted expression and spatial distribution of truncating Magel2 transcripts in the brain were maintained. Although neonatal mice were lighter than wildtype littermates, males and females weighed the same as their wildtype littermates by eight and four weeks of age, respectively. However, they did not show arthrogryposis and severe developmental delay. Collectively, the genome-edited mouse model maintains genomic imprinting and distribution of truncated Magel2 transcripts in the brain, but only partially recapitulates SYS phenotypes.

Academic Significance and Societal Importance of the Research Achievements

本研究では、Schaaf-Yang症候群（SYS)患者のモデルとなるフレームシフト変異によるモデルマウスの作成に世界に先駆けて成功した。主に乳児期のみに哺乳不良が認められるSYSのヒトでの表現型を再現できたが、関節拘縮や重度精神運動発達遅滞は再現できなかった。表現型の一部しか示せず、治療法に関する検討まではできなかったが、新しいモデルマウスはSYSの病態解明に重要な役割を果たすことが期待できると考えられ、学術的意義は大きいと考えられた。

Research Products

• [Journal Article] Two mouse models carrying truncating mutations in Magel2 show distinct phenotypes (2020)
  • Author(s): Ieda Daisuke、Negishi Yutaka、Miyamoto Tomomi、Johmura Yoshikazu、Kumamoto Natsuko、Kato Kohji、Miyoshi Ichiro、Nakanishi Makoto、Ugawa Shinya、Oishi Hisashi、Saitoh Shinji
  • Journal Title: PLOS ONE Volume: 15 Issue: 8 Pages: e0237814-e0237814
  • DOI: 10.1371/journal.pone.0237814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy (2019)
  • Author(s): Negishi Yutaka、Ieda Daisuke、Hori Ikumi、Nozaki Yasuyuki、Yamagata Takanori、Komaki Hirofumi、Tohyama Jun、Nagasaki Keisuke、Tada Hiroko、Saitoh Shinji
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 14 Issue: 1 Pages: 277-277
  • DOI: 10.1186/s13023-019-1249-4
  • Peer Reviewed / Open Access
• [Presentation] Generation of a mouse model carrying mutation in Magel2 (2019)
  • Author(s): Daisuke Ieda, Yutaka Negishi, Tomomi Miyamoto, Natsuko Kumamoto, Kohji Kato, Shinya Ugawa, Hisashi Oishi, Shinji Saitoh
  • Organizer: 第61回日本小児神経学会学術集会 日本-台湾 新生児・小児神経ワークショップ
• [Presentation] Schaaf-Yang症候群の臨床像検討とトランスジェニックマウスを用いた病態解析 (2018)
  • Author(s): 根岸豊, 家田大輔, 中村勇治, 堀いくみ, 服部文子, 野崎靖之, 小牧宏文, 遠山潤, 長崎啓佑, 多田弘子, 大石久史, 齋藤伸治
  • Organizer: 第60回日本小児神経学会学術集会