Pathophysiological analysis and development of therapeutic procedures for citrin deficiency by using a mouse model

2008 Fiscal Year Final Research Report

• Project/Area Number: 19591230
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokushima Bunri University
• Principal Investigator: SAHEKI Takeyori Tokushima Bunri University, 健康科学研究所, 教授 (10056070)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Keiko 鹿児島大学, 大学院医歯学総合研究科・病態医化学分野, 准教授 (70108869) ; KUHARA Tomiko 金沢医科大学, 総合医学研究所人類遺伝学研究部門, 教授 (30080568)
• Project Period (FY): 2007 – 2008
• Keywords: 先天代謝異常症 / モデル動物 / アスパラギン酸・グルタミン酸ミトコンドリア膜輸送体 / シトリン / 病態解析 / 治療法

Research Abstract

新生児期には、肝内胆汁うっ滞、多種アミノ酸血症、ガラクトース血症などを、成人期では高アンモニア血症を伴う成人発症II型シトルリン血症を発症するシトリン(肝型アスパラギン酸・グルタミン酸ミトコンドリア膜輸送体)欠損症のモデルマウスを作成した。本研究では、その病態を解析し、アミノ酸、尿素合成異常だけでなく、糖代謝異常が大きな役割を果たしていることを明らかにし、ピルビン酸ナトリウムやアミノ酸混合物が、疾患モデルマウスの病態改善に有効であることを見いだした。さらに、ショ糖投与後、肝臓において解糖系中間体濃度が著しく増加することを見いだした。本現象は、今後有効な治療薬検定における有効なマーカーになる得るものと考えている。

Research Products

• [Journal Article] Sustaining hyper- citrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2, citrin deficiency, even during the silent period (2009)
  • Author(s): Nagasaka H, Kobayashi K (8番), Saheki T (9番), Yorifuji T
  • Journal Title: Mol Genet Metab 97 Pages: 21-26
  • Peer Reviewed
• [Journal Article] Neonatal intrahepatic cholestasis caused by citrin deficiency: Clinical and laboratory investigation of 13 subjects in mainland of China (2009)
  • Author(s): Song YZ, Kobayashi K (10番), Saheki T (11番), Zheng XY
  • Journal Title: Dig Liver Dis Pages: 0
  • Peer Reviewed
• [Journal Article] Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate (2008)
  • Author(s): Mutoh K, Kurokawa K, Kobayashi K, Saheki T
  • Journal Title: J Inherit Metab Dis (Epub ahead of print) Pages: 0
  • Peer Reviewed
• [Journal Article] Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease (2008)
  • Author(s): Komatsu M, Saheki T (10番), Aoyama T, Kobayashi K (12番)
  • Journal Title: J Hepatol 49 Pages: 810-820
  • Peer Reviewed
• [Journal Article] Reduced carbohydrate intake in citrin-deficient subjects (2008)
  • Author(s): Saheki T, Kobayashi K, Terashi M, Ohura T, Yanagawa Y, Okano Y, Hattori T, Fujimoto H, Mutoh K, Kizaki Z, Inui A
  • Journal Title: J Inherit Metab Dis 31 Pages: 386-394
  • Peer Reviewed
• [Journal Article] Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency (2008)
  • Author(s): Tabata A, Saheki T (11番), Kobayashi K (12番)
  • Journal Title: J Hum Genet 53 Pages: 534-545
  • Peer Reviewed
• [Journal Article] Primary liver carcinoma exhibiting dual hepatocellular-biliary epithelial differentiations associated with citrin deficiency: a case report (2008)
  • Author(s): Soeda J, Kobayashi K (8番), Saheki T (9番), Kojiro M, Miyagawa S
  • Journal Title: J Clin Gastroenterol 42 Pages: 855-860
  • Peer Reviewed
• [Journal Article] Six cases of citrin deficiency in Korea (2008)
  • Author(s): Ko JM, Saheki T (7番), Kobayashi K (8番), Yoo HW
  • Journal Title: Int J Mol Med 20 Pages: 809-815
  • Peer Reviewed
• [Journal Article] Citrin/mitochondrial glycerol 3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency (2007)
  • Author(s): Saheki T, Iijima M, Li MX, Kobayashi K, Horiuchi M, Ushikai M, Okumura F, Meng XJ, Inoue I, Tajima A, Moriyama M, Eto K, Kadowaki T, Sinasac DS, Tsui LC, Tsuji M, Okano A, Kobayashi T
  • Journal Title: J Biol Chem 282 Pages: 25041-25052
  • Peer Reviewed
• [Journal Article] Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) (2007)
  • Author(s): Ohura T, Kobayashi K, Tazawa Y, Abukawa D, Sakamoto O, Tsuchiya S, Saheki T
  • Journal Title: J Inherit Metab Dis 30(2) Pages: 139-144
  • Peer Reviewed
• [Journal Article] Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet (2007)
  • Author(s): Dimmock D, Kobayashi K, Iijima M, Tabata A, Wong LJ, Saheki T, Lee B, Scaglia F
  • Journal Title: Pediatrics 119 Pages: e773-777
  • Peer Reviewed
• [Presentation] Citrin/mGPDH ダブルKOマウスを用いるシトリン欠損症の治療法の開発 (2008)
  • Author(s): 佐伯武頼, 小林圭子, 飯島幹雄
  • Organizer: 第50回日本先天代謝異常学会総会・第7回アジア先天代謝異常学会
  • Place of Presentation: 米子
  • Year and Date: 20081106-8
• [Presentation] Citrin deficiency: Pathophysiology and issues of its treatment(招待講演) (2008)
  • Author(s): Saheki T, Kobayashi K
  • Organizer: The Celebration Ceremony for the 10th Anniversary of CJCP & the 2008 National Conference on Pediatric Hotspot
  • Place of Presentation: Changsha, Hunan, China
  • Year and Date: 20080917-21
• [Presentation] A newly-established disease entity, citrin deficiency(教育講演) (2008)
  • Author(s): Saheki T, Kobayashi K
  • Organizer: The 11th Asian-European Workshop on Inborn Errors of Metabolism (AEWIEM)
  • Place of Presentation: Seoul and Jeju, Korea
  • Year and Date: 20080418-23
• [Presentation] Citrin deficiency: Pathophysiology and issues of its treatment (2008)
  • Author(s): Saheki T, Kobayashi K
  • Organizer: AASPP-Seminar on Citrin Deficiency in Vietnam jointed with Pediatric Society Meeting of HCMC
  • Place of Presentation: Ho Chi Minh City, Vietnam
  • Year and Date: 2008-06-26
• [Presentation] Pathophysiology and nutritional aspect of citrin deficiency(招待講演) (2007)
  • Author(s): Saheki T, Kobayashi K
  • Organizer: 10th Military Annual Meeting on Pediatrics and 3rd National Conference on Pediatric Hotspots
  • Place of Presentation: 中国・内モンゴル自治区・呼和浩特市
  • Year and Date: 20070817-20