Molecular genetics of citrin deficiency and search for the genetic and/or environmental factor(s) concerned with onset of various symptoms

2009 Fiscal Year Final Research Report

• Project/Area Number: 19390096
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human genetics
• Research Institution: Kagoshima University
• Principal Investigator: KOBAYASHI Keiko Kagoshima University, 大学院・医歯学総合研究科, 准教授 (70108869)
• Co-Investigator(Kenkyū-buntansha): IIJIMA Mikio 鹿児島大学, 大学院・医歯学総合研究科, 助教 (00305111) ; SAHEKI Takeyori 徳島文理大学, 健康科学研究所, 教授 (10056070) ; NAKAGAWA Shiro 鹿児島大学, 大学院・医歯学総合研究科, 教授 (70073666)
• Project Period (FY): 2007 – 2009
• Keywords: Citrin / SLC25A13 / 成人発症II型シトルリン血症(CTLN2) / 胆汁うっ滞性新生児肝炎(NICCD) / aspartate-glutamate carrier / NADH shuttle / malate-aspartate shuttle / glycerophosphate shuttle

Research Abstract

Major phenotypes of citrin deficiency are cholestatic neonatal hepatitis (NICCD) and adult-onset type II citrullinemia (CTLN2). In the present study, we found that the children with citrin deficiency at the silent (apparently healthy) stage were persistently in oxidative stress and had urea cycle dysfunction and hypercholesterolemia. One of the most prominent characteristics of citrin deficiency is the unique food preference ; citrin deficient-subjects like protein-/fat-rich foods and dislike carbohydrate-rich foods. Our present study also indicated that this food preference seems to be closely related to the pathogenesis such as CTLN2-onset and therapy. It is, however, still difficult to clarify the mechanism of hepatocellular carcinoma-onset in citrin deficiency.

Research Products

• [Journal Article] Citrin deficiency and current treatment concepts. (2010)
  • Author(s): Saheki T, Inoue K, Tushima A, Mutoh K, Kobayashi K
  • Journal Title: Mol Genet Metab 100 Pages: S59-S64
  • Peer Reviewed
• [Journal Article] Sustaining hypercitrullinemia, 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, Okano Y, Tsukahara H, Shigematsu Y, Momoi T, Yorifuji J, Miida T, Ohura T, Kobayashi K, Saheki T, Hirano K, Takayanagi M, Yorifuji T
  • Journal Title: Mol Genet Metab 97(1) Pages: 21-26
  • Peer Reviewed
• [Journal Article] Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinemia 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)
  • 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, Sheng J-S, Ushikai M, Song Y-Z, Gao H-Z, Lu Y-B, Okumura F, Iijima M, Mutoh K, Kishida S, Saheki T, Kobayashi K
  • Journal Title: J Hum Genet 53(6) Pages: 534-545
  • 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(3) Pages: 386-394
  • Peer Reviewed
• [Journal Article] Citrin deficiency (2008)
  • Author(s): Kobayashi K, Saheki T
  • Journal Title: in GeneReviews at GeneTests: Medical Genetics Information Resource
  • 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, Yazaki M, Nakata T, Miwa S, Ikeda S, Hosoda W, Iijima M, Kobayashi K, Saheki T, Kojiro M, Miyagawa S
  • Journal Title: J Clin Gastroenterol 42(7) Pages: 855-860
  • Peer Reviewed
• [Journal Article] Overview of citrin deficiency: SLC25A13 mutations and the frequency. (2008)
  • Author(s): Kobayashi K, Ushikai M, Song Y-Z, Gao H-Z, Sheng J-S, Tabata A, Okumura F, Ikeda S, Saheki T
  • Journal Title: J Applied Clin Pediatr 23(20) Pages: 1553-1557
  • Peer Reviewed
• [Journal Article] Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. (2008)
  • Author(s): Komatsu M, Yazaki M, Tanaka N, Sano K, Hashimoto E, Takei Y, Song Y-Z, Tanaka E, Kiyosawa K, Saheki T, Aoyama T, Kobayashi K
  • Journal Title: J Hepatol 49(5) Pages: 810-820
  • 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: Inherit Metab Dis 30(2) Pages: 139-144
  • 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 L-C, Tsuji M, Okano A, Kobayashi T
  • Journal Title: J Biol Chem 282(34) Pages: 25041-25052
  • Peer Reviewed
• [Journal Article] Downregulation of citrin, a mitochondrial AGC, is associated with apoptosis of hepatocytes. (2007)
  • Author(s): Sawada S, Kinjo T, Makishi S, Tomita M, Arasaki A, Iseki K, Watanabe H, Kobayashi K, Sunakawa H, Iwamasa T, Mori N
  • Journal Title: Biochem Biophys Res Commun 364(4) Pages: 937-944
  • Peer Reviewed
• [Presentation] Pathophysiology and therapy of citrin deficiency: consideration from analysis of the model mice (2010)
  • Author(s): Saheki T, Kobayashi K
  • Organizer: The 1st Asian Congress for Inherited Metabolic Diseases (ACIMD): Plenary Lecture
  • Place of Presentation: Fukuoka
  • Year and Date: 20100507-20100510
• [Presentation] Overview of citrin deficiency: The distribution and frequency of SLC25A13 mutations (2010)
  • Author(s): Kobayashi K, Ushikai M, Saheki T
  • Organizer: The 1st Asian Congress for Inherited Metabolic Diseases (ACIMD): Citrin AASPP-Workshop
  • Place of Presentation: Fukuoka
  • Year and Date: 20100507-20100510
• [Presentation] Citrin deficiency and current treatment concepts (2009)
  • Author(s): Saheki T, Kobayashi K
  • Organizer: Satellite Symposium to the 11th International Congress on Inborn Errors of Metabolism: Overcoming Barriers-New Developments and Future Directions for Urea Cycle Disorders
  • Place of Presentation: La Jolla, USA
  • Year and Date: 20090827-20090829
• [Presentation] シトリン欠損症原因遺伝子の発見が臨床に与えたインパクト (2009)
  • Author(s): 佐伯武頼, 小林圭子
  • Organizer: 第33回日本遺伝カウンセリング学会
  • Place of Presentation: 西宮
  • Year and Date: 20090724-20090726
• [Presentation] Distribution and frequency of citrin deficiency with SLC25A13 mutations (2008)
  • Author(s): Kobayashi K, Ushikai M, Sheng J-S, Song Y-Z, Gao H-Z, Okumura F, Ikeda S, Saheki T
  • Organizer: The 11th Asian-European Workshop on Inborn Errors of Metabolism (AEWIEM)
  • Place of Presentation: Seoul and Jeju, Korea
  • Year and Date: 20080418-20080423
• [Presentation] 国内外のシトリン欠損症におけるSLC25A13変異と頻度 (2007)
  • Author(s): 小林圭子, 牛飼美晴, 盛建勝, 宋元宗, 奥村史彦, 池田さやか, 飯島幹雄, 佐伯武頼
  • Organizer: 日本人類遺伝学会第52回大会
  • Place of Presentation: 東京
  • Year and Date: 20070912-20070915
• [Presentation] Overview of Citrin Deficiency: SLC25A13 Mutations and the Frequency (2007)
  • Author(s): Kobayashi K, Ushikai M, Sheng J-S, Song Y-Z, Okumura F, Tabata A, Saheki T
  • Organizer: The 2nd International Symposium on Citrin Deficiency
  • Place of Presentation: Haikou-Hainan
  • Year and Date: 20070827-20070828
• [Presentation] Overview of citrin deficiency and the frequency (2007)
  • Author(s): 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: 20070817-20070820
• [Presentation] Pathophysiology and nutritional aspect of citrin deficiency (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: 20070817-20070820