Diagnostic method for inborn errors of pyrimidine metabolism

• Project/Area Number: 26860818
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Fujita Health University
• Principal Investigator: NAKAJIMA Yoko 藤田保健衛生大学, 医学部, 助教 (70598309)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: ピリミジン代謝異常症 / 尿中ピリミジン代謝物分析 / 5-フルオロウラシル / ハイリスクスクリーニング / UPLC-MS/MS / 遺伝子診断 / 先天性ピリミジン代謝異常症診断システム / 5FU関連抗癌剤代謝 / 5FU薬物代謝 / ハイリスクスクリーニンング

Outline of Final Research Achievements

Inborn errors of pyrimidine degradation pathway have wide clinical aspects and show very severe side effects of 5-fluorouracil related anticancer drugs. However, the details of these diseases, such as disease frequency or genetic mutations are unclear, because the number of reported patients is limited.
In this study, we established the diagnostic system for inborn errors of pyrimidine degradation pathway by simultaneous analysis of urinary pyrimidine metabolites using UPLC-MS/MS followed by genetic analysis. The genetic analysis revealed that UPB1 R326Q mutation was identified in all patients with beta-ureidopropionase deficiency and 70% of these patients were homozygote of this mutation. Population study showed that 2% of healthy Japanese were carrier of the R326Q mutation. This result showed that beta-ureidopropionase deficiency is not as rare as generally considered in Japan.

Research Products

• [Int'l Joint Research] Academic Medical Center(オランダ)
• [Journal Article] Altered Pre-mRNA Splicing Caused by a Novel Intronic Mutation c.1443+5G>A in the Dihydropyrimidinase (DPYS) Gene. (2016)
  • Author(s): Nakajima Y, Meijer J, Zhang C, Wang X, Kondo T, Ito T, Dobritzsch D, Van Kuilenburg AB.
  • Journal Title: Int J Mol Sci. Volume: 17(1) Issue: 1 Pages: 86-8
  • DOI: 10.3390/ijms17010086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] UPLC-MS/MS によるピリミジン代謝異常症スクリーニング法につい (2015)
  • Author(s): 前田康博，中島葉子，伊藤哲哉
  • Journal Title: Japanese Society for Biomedical Mass Spectrometry Volume: Vol. 40 No.1 Pages: 4-10
• [Journal Article] Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation (2014)
  • Author(s): Nakajima Y, Meijer J, Dobritzsch D, Ito T, Meinsma R, Abeling NGGM, Roelofsen J, Zoetekouw L, Watanabe Y, Lee T, Mitsubuchi H, Yoneyama A, Ohta K, Kuhara T, Eto K, Saito K, van Kuilenburg ABP
  • Journal Title: J Inherit Metab Dis Volume: 37 Issue: 5 Pages: 801-812
  • DOI: 10.1007/s10545-014-9682-y
  • Peer Reviewed / Open Access
• [Presentation] β-ウレイドプロピオナーゼ欠損症30例における分子遺伝学解析： 東南アジアにおけるコモン変異R326Qの発見 (2015)
  • Author(s): 中島葉子, Judith Meijer, 張春花, 渡邊順子, 久原とみ子,伊藤哲哉, André B.P. van Kuilenburg
  • Organizer: 第60回日本人類遺伝学会
  • Place of Presentation: 東京 京王プラザホテル
  • Year and Date: 2015-10-14
• [Presentation] UPLC-MS/MSによるピリミジン塩基代謝物の定量によるピリミジン代謝異常症スクリーニング (2015)
  • Author(s): 前田康博、後藤加奈、中島葉子、前田葉子、堀田祐志、片岡智哉、川出義浩、伊藤哲哉、木村和哲
  • Organizer: 第40回日本医用マススペクトル学会
  • Place of Presentation: 浜松 アクトシティ浜松 コングレスセンター
  • Year and Date: 2015-09-17
• [Presentation] Clinical, biochemical and molecular analysis of 30 children with β-ureidoproionase deficiency demonstrates high prevalence of the c.977G>A(p.R326Q) mutation (2015)
  • Author(s): Yoko Nakajima, Judith Meijer, Chunhua Zhang, Yoriko Watanabe, Tomoko Lee, Hiroshi Mitsubuchi, Kaoru Eto, Tomiko Kuhara, Tetsuya Ito, Andre van Kuilenburg
  • Organizer: 16th international Symposium on Purine and Pyrimidine Metabolism in Man
  • Place of Presentation: New York, Columbia University
  • Year and Date: 2015-06-06
  • Int'l Joint Research
• [Presentation] High prevalence of the mutation R326Q in 30 children with β-ureidoproionase deficiency in East Asia (2015)
  • Author(s): Yoko Nakajima, Judith Meijer, Chunhua Zhang, Yoriko Watanabe, Tomoko Lee, Hiroshi Mitsubuchi, Kaoru Eto, Tomiko Kuhara, Tetsuya Ito, Andre van Kuilenburg
  • Organizer: 第57回日本小児神経学会
  • Place of Presentation: 大阪 帝国ホテル
  • Year and Date: 2015-05-28
• [Presentation] Clinical, biochemical and molecular analysis of 30 children with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G>A (p.R326Q) mutation (2015)
  • Author(s): Yoko Nakajima, Judith Meijer, Doreen Dobritzsch, Chunhua Zhang, Tetsuya Ito, Yoriko Watanabe, Tomiko Kuhara, and André B.P. van Kuilenburg
  • Organizer: The 4th Asiaan Congress for Inherited Metabolic diseases
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-03-19 – 2015-03-22
• [Presentation] β-ウレイドプロピオナーゼ欠損症13例の生化学的・分子生物学的解析とUPB1遺伝子p.R326Q変異頻度の検討 (2014)
  • Author(s): Yoko Nakajima, Judith Meijer, Doreen Dobritzsch, Yoriko Watanabe, Tomiko Kuhara, Hiroshi Mitsubuchi, Tomoko Lee, Kaoru Eto, Tetsuya Ito, André B.P. van Kuilenburg
  • Organizer: 第56回 日本先天代謝異常学会総会 / 第12回アジア先天代謝異常症シンポジウム
  • Place of Presentation: 宮城県仙台市 江陽グランドホテル
  • Year and Date: 2014-11-13 – 2014-11-15
• [Presentation] Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G>A (p.R326Q) mutation (2014)
  • Author(s): Yoko Nakajima, Judith Meijer, Doreen Dobritzsch, Tetsuya Ito, Rutger Meinsma, Lida Zoetekouw, Yoriko Watanabe, Kyoko Tashiro, Tomoko Lee, Yasuhiro Takeshima, Hiroshi Mitsubuchi, Akira Yoneyama, Kazuhide Ohta, Kaoru Eto, Kayoko Saito, Tomiko Kuhara, A.B.P. van Kuilenburg
  • Organizer: SSIEM Annual Symposium 2014
  • Place of Presentation: Innsbruck, Tyrol, Austria.
  • Year and Date: 2014-09-02 – 2014-09-05
• [Remarks] 愛知県小児臨床研究会 Aichi Pediatric Clinical Study
  • URL: http://www.med.nagoya-u.ac.jp/apecs/