The mechanism of severe developmental disorders caused by abnormalities in UFM1 system

• Project/Area Number: 18K15061
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Juntendo University (2019); Niigata University (2018)
• Principal Investigator: Ishimura Ryosuke 順天堂大学, 医学部, 助教 (00816960)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: UFM1 / UBA5 / ユビキチン様修飾システム / 発達障害 / CYB5R3 / ユビキチン様タンパク質 / ユビキチン用修飾システム / ユビキチン様修飾

Outline of Final Research Achievements

We have shown genetic mutations related to the UFM1 system lead to severe developmental disorders such as epilepsy and microcephaly when the UFM1 system activity is reduced. However, since the causative target molecule of UFM1 has not been identified, its molecular mechanism was unclear. NADH-Cytocrome b5 Reductase 3 (CYB5R3) was identified as a new target gene of UFM1 by using mass spectrometry.

Academic Significance and Societal Importance of the Research Achievements

これまでにUFM1システム関連遺伝子に変異を持つ遺伝性重度発達障害家系を特定してきたが、UFM1の基質が不明であり、詳細が不明であった。本研究では新たなUFM1の基質を同定した。この基質自身の変異もUFM1システム関連遺伝子の変異による疾患と同様の症状を示す。UFM1システムの修飾低下が病気の発症となるため、この基質への修飾を促進することで治療法の開発につながりうる。

Research Products

• [Journal Article] A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy (2020)
  • Author(s): Cabrera-Serrano Macarena、Coote David Joseph、Azmanov Dimitar、Goullee Hayley、Andersen Erik、McLean Catriona、Davis Mark、Ishimura Ryosuke、Stark Zornitza、Vallat Jean-Michel、Komatsu Masaaki、Kornberg Andrew、Ryan Monique、Laing Nigel G、Ravenscroft Gina
  • Journal Title: Journal of Medical Genetics Volume: - Issue: 12 Pages: 835-842
  • DOI: 10.1136/jmedgenet-2019-106496
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. (2018)
  • Author(s): Nahorski MS, Maddirevula S, Ishimura R, Alsahli S, Brady AF, Begemann A, Mizushima T, Guzman-Vega FJ, Obata M, Ichimura Y, Alsaif HS, Anazi S, Ibrahim N, Abdulwahab F, Hashem M, Monies D, Abouelhoda M, Meyer BF, Alfadhel M, Eyaid W, Zweier M, Steindl K, Rauch A, Arold ST, Woods CG, Komatsu M, Alkuraya FS.
  • Journal Title: Brain Volume: 141 Issue: 7 Pages: 1934-1945
  • DOI: 10.1093/brain/awy135
  • Peer Reviewed / Open Access / Int'l Joint Research