Pathophysiological study and the developments of therapy using mouse model of glutamate dehydrogenase disorder

• Project/Area Number: 24591522
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hyogo Medical University
• Principal Investigator: OKANO YOSHIYUKI 兵庫医科大学, 医学部, 非常勤講師 (60231213)
• Co-Investigator(Kenkyū-buntansha): TOKUHARA Daisuke 大阪市立大学, 医学(系)研究科, 講師 (60448751)
• Co-Investigator(Renkei-kenkyūsha): MORITA Takashi 大阪市立大学, 大学院医学研究科, 教授 (70150349) ; SAHEKI Takeyori 熊本大学, 生命資源研究・支援センター, 特任教授 (10056070)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: グルタミン酸脱水素酵素 / 高アンモニア血症 / 高インスリン血症 / 動物モデル / 遺伝子 / 酵素 / 肝臓 / インスリン / アンモニア / 低血糖 / グルタメイト脱水素酵素 / トランスジェニックマウス

Outline of Final Research Achievements

Hyperinsulinism hyperammonemia is caused by dysregulation of GDH activity, which induces insensitivity for GTP inhibition and the unregulated insulin secretion. We have made a transgenic mouse (TGM) to clarify the mechanism of hyperammonemia and to develop the therapy. The hetero-TGM showed an increase of GDH activity, mild hypoglycemia, and mild hyperammonemia, however no clinical symptoms. In metabolome analysis of the liver, brain, heart, and kidney; fatty acid metabolites were enhanced in all the organs. The substances before α-oxoglutarate decreased and the substances afterα-oxoglutarate increased in the glycolytic system and TCA cycle of the liver. Because of the increased Gln/Glu, decreased Orn, Cit, and As, and no decreased N-acetylglutamate, hyperamonemia is not caused by the reduction of carbamoyl phosphate synthase. We have to consider a new mechanism for hyperammonemia.

Research Products

• [Journal Article] The importance of molecular diagnosis in the accurate diagnosis of systemic carnitine deficiency (2015)
  • Author(s): Hitomi T, Matsuura N, Yosuke Shigematsu S, Okano Y, Shinozaki E, Kawai M, Kobayashi H, Harada K. H. Koizumi K.
  • Journal Title: J. Genet Volume: 94 Pages: 147-150
  • Peer Reviewed
• [Journal Article] Role of per-rectal portal scintigraphy in long-term follow-up of congenital portosystemic shunt. (2014)
  • Author(s): Cho Y, Tokuhara D, Shimono T, Yamamoto A, Higashiyama S, Kotani K, Kawabe J, Okano Y, Shiomi S, Shintaku H
  • Journal Title: Pediatr Res. Volume: 75 Pages: 658-662
  • Peer Reviewed
• [Journal Article] Changes of lipoproteins in phenylalanine hydroxylase-deficient children for the first early of life. (2014)
  • Author(s): Nagasaka H, Tsukahara H, Okano Y, Hirano K, Sakurai T, Hui S-P, Ohura T, Usui H, Yorifuji T, Hirayama S, Ohtake A, Miida T.
  • Journal Title: Clin Chim Acta Volume: 印刷中 Pages: 1-4
  • DOI: 10.1016/j.cca.2014.02.020
  • Peer Reviewed
• [Journal Article] Optimal serum phenylalanine for adult patients with phenylketonuria. (2013)
  • Author(s): Okano Y, Nagasaka H.
  • Journal Title: Mol Genet Metab Volume: 110 Issue: 4 Pages: 424-430
  • DOI: 10.1016/j.ymgme.2013.09.007
  • Peer Reviewed
• [Journal Article] Fatigue and quality of life in citrin deficiency during adaptation and compensation stage. (2013)
  • Author(s): Okano Y, Kobayashi K, Ihara K, Ito T, Yoshino M, Watanabe Y, Kaji S, Ohura T, Nagao M, Noguchi A, Mushiake S, Hohashi N, Hashimoto-Tamaoki T
  • Journal Title: Mol Genet Metab. Volume: 109(1) Issue: 1 Pages: 9-13
  • DOI: 10.1016/j.ymgme.2013.01.020
  • Peer Reviewed
• [Journal Article] Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations. (2012)
  • Author(s): Chiu YH, Chang YC, Chang YH, Niu DM, Yang YL, Ye J, Jiang J, Okano Y, Lee DH, Pangkanon S, Kuptanon C, Hock NL, Chiong MA, Cavan BV, Hsiao KJ, Liu TT.:
  • Journal Title: J Hum Genet Volume: 57 Issue: 2 Pages: 145-152
  • DOI: 10.1038/jhg.2011.146
  • NAID: 10030711780
  • Peer Reviewed
• [Journal Article] Intractable absence seizures in hyperinsulinism-hyperammonemia syndrome. (2012)
  • Author(s): Nakano K, Kobayashi K, Okano Y, Aso K, Ohtsuka Y
  • Journal Title: Pediatr Neurol. Volume: 47 Issue: 2 Pages: 119-122
  • DOI: 10.1016/j.pediatrneurol.2012.04.019
  • Peer Reviewed
• [Journal Article] Oxysterol changes along with cholesterol and vitamin D changes in adult phenylketonuric patients diagnosed by newborn mass-screening (2012)
  • Author(s): Nagasaka Hironori, et al.
  • Journal Title: Clinica Chimica Acta Volume: 416 Pages: 54-59
  • DOI: 10.1016/j.cca.2012.10.011
  • Peer Reviewed