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2001 Fiscal Year Final Research Report Summary

Functional analysis of novel gene products, citrin and aralar

Research Project

Project/Area Number 12670143
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionKagoshima University

Principal Investigator

IIJIMA Mikiko  Kagoshima University, Faculty of Medicine, Research Associate, 医学部, 助手 (00305111)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Keiko  Kagoshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (70108869)
SAHEKI Takeyori  Kagoshima University, Faculty of Medicine, Professor, 医学部, 教授 (10056070)
Project Period (FY) 2000 – 2001
Keywordscitrullinemia / citrin / aralar / aspartate glutamate carrier / SLC25A13 / SLC25A12 / mitochondria
Research Abstract

A novel gene, SLC25A13, was identified by homozygosity mapping and positional cloning as the responsible for adult-onset type II citrullinemia (CTLN2). The overall structure of citrin is very similar to that of aralar, encoded by the gene SLC25A12. In this project we have studied the function of citrin and aralar for use in elucidation of crisis mechanism, diagnosis and treatment of CTLN2.
Citrin was distributed mainly in the liver, kidney, heart and newborn small intestine. Aralar was expressed in diaphragm, skeletal muscle, heart, brain, and kidney, but not in the liver. It is important for the liver-specific disorder of citrin deficiency, CTLN2, to note that the liver is the only organ expressing citrin in large amounts, but that it dose not express aralar. Citrin and aralar localized to mitochondrial inner membrane were found to be isoforms of mitochondrial aspartate glutamate carriers (AGC) with active AGC activity in their C-half domains and EF-hand Ca binding in their N-terminal … More dpmains. The AGC is an essential component of malate aspartate (NADH) shuttle. The main function of the shuttle is the transport of NADH )reducing equivalent) from cytosol to mitochondria. The AGC is also important for urea synthesis from ammonia, because aspartate formed from ammonia via glutamate in the mitochondria should go out to cytosol through AGC and be supplied for argininosuccinate synthetase. These result suggest that either or both of these effects could lead to the symptoms of CTLN2.
In order to identify the protein that interact with citrin, we screened cDNA library derived from human liver by using yeast two hybrid system. After sequencing analysis, we have identified two proteins, one is a protein which regulats Ca effect of protein kinase C, and the other is a redox related protein. The precise characterization of interaction between citrin and these protein needs to be assessed. Expression of mutated citrin and GFP fusion proteins, in which most oftransmembrane domain is retained, showed a punctuate pattern of distribution that colocalized with mitochondria selective dye, MitoTracker Red CMXRos. Further study is required to determine whether this mitochondrial punctuation induces cell death process, apoptosis. Less

  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Yasuda T et al.: "Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia"Hum. Genet.. 107. 537-545 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小林圭子: "生化学遺伝学と代謝異常症"病理と臨床. 18. 685-690 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小林圭子: "シトルリン血症の遺伝子診断<Editorial>"肝臓. 41. 543-549 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kasahara M et al.: "Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor"Transplantation. 71. 157-159 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ohura T et al.: "Neonatal presentation of adult-onset type II citrullinemia"Hum. Genet.. 108. 87-90 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maruyama H et al.: "Citrullinemia type II in a 64year-old man with fluctuating serum citrulline levels"J. Neurol. Sci.. 182. 167-170 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hwu WL et al.: "A Chinese adult onset type II citrullinaemia patient with 851del4/1638ins23 mutations in the SLC25A13 gene"J. Med. Genet.. 38. E23 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuboi Y et al.: "High serum pancreatic secretory trypsin inhibitor before onset of type II citrullinemia"Neurology. 57. 933 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tazawa Y et al.: "Infantile cholestatic jaundice associated with adult-onset type II citrullinemia"J. Pediatr.. 138. 735-740 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tomomasa T et al.: "Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy"J. Pediatr.. 138. 741-743 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Palmieri L et al.: "Citrin and aralar1 are Ca^<2+>-stimulated aspartate/glutamate transporters in mitochondria"EMBO J.. 20. 5060-5069 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Iijima M et al.: "Pathogenesis of adult-onset type II citrullinemia caused by deficiency of citrin, a mitochondrial solute carrier protein : tissue and subcellular localization of citrin"Advanees in Enzyme Regulation. 41. 325-342 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ikeda S et al.: "Type II (adult onset) citrullinaemia : clinical pictures and the therapeutic effect of liver transplantation"J. Neurol. Neurosurg. Psychiatry. 71. 663-667 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maruyama H et al.: "Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels : mutations in the SLC25A13 gene"J. Neurol. Sci.. 193. 63 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小林圭子: "シトルリン血症とその遺伝子診断"検査と技術. 29. 302-304 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小林圭子: "Citrin欠損症(基礎):SLC25A13遺伝子変異がもたらす疾患とその病態"日本マス・スクリーニング学会誌. 11. 17-22 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 大浦敏博: "Citrin欠損症(臨床):新生児マススクリーニングを契機に発見されたcitrin欠損による新生児肝内胆汁うっ帯症:9症例の臨床像の検討"日本マス・スクリーニング学会誌. 11. 23-27 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamaguchi N et al.: "Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population : identification of two novel mutations and establishment of multipe DNA diagnosis methods for nine mutations"Hum. Mutat.. 19. 122-130 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oshiro S et al.: "A patient with adult-onset type II citrullinemia on long-term hemodialysis : reversal of clinical symptoms and brain MRI findings"Am. J. Kidney Dis.. 39. 189-192 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Begum L et al.: "Expression of three mitochondrial solute carriers, citrin, aralar1 and ornithine transporter, in relation to urea cycle in mice"Biochem. Biophys.Acta. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Saheki T et al.: "Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency"Metab. Brain Dis.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kobayashi K et al.: "Calcium : The Molecular Basis of Calcium Action in Biology and Medicine"Pochet R., Donato R., Haiech J., Heizmann C. and Gerke V. (eds) Kluwer Academic Publishers, Dordrecht. 732(565-587) (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 小林圭子: "成人発症II型シトルリン血症.最新肝臓病学"渡辺明治、樋口清博編集,新興医学出版,東京. 255(131-135) (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yasuda,T. et al.: "Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia"Hum. Genet.. 107. 537-545 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kobayashi,K.: "Calcium: The Molecular Basis of Calcium Action in Biology and medicine"Pochet R., Donato R., Haiech J., Heizmann C. and Gerke V. )eds) Kluwer Academic Publishers, Dordrecht. 565-587 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kasahara,M. et al.: "Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor"Transplantation. 71. 157-159 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ohura,T. et al.: "Neonatal presentation of adult-onset type II citrullinemia"Hum. Genet.. 108. 87-90 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Maruyama,H. et al.: "Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels"J. Neurol. Sci.. 182. 167-170 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hwu,WL. et al.: "A Chinese adult-onset type II citrullinemia patient with 851del4/1638ins23 mutations in SLC25A13 gene"J. Med. Genet.. 38. E23 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuboi,Y. et al.: "High serum pancreatic secretory trypsin inhibitor before onset of type II citrullinemia"Neurology. 57. 933 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tazawa,Y. et al.: "Infantile cholestatic jaundice associated with adult-onset type II citrullinemia"J. Pediatr.. 138. 735-740 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tomomasa,T. et al.: "Possible clinical and histologic manifestations of adult-onset type II citrullinemia in early infancy"J. Pediatr.. 138. 741-743 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Palmieri,L. et al.: "Citrin and aralarl are Ca^<2+>- stimulated aspartate/glutamate transporters in mitochondria"EMBO J.. 20. 5060-5069 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Iijima,M. et al.: "Pathogenesis of adult-onset type II citrullinemia caused by deficiency of citrin, a mitochondrial solute carrier protein: tissue and subcellular localization of citrin"Adv. Enzyme Regul.. 41. 325-342 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ikeda,S. et al.: "Type II )adult-onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation"J. Neurol. Neurosurg. Psychiatry. 71. 663-670 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Maruyama,H. et al.: "Citrullinemia type II in a 64-year-old man with fluctuating serum citrulline levels: mutations in the SLC25A13 gene"J. Neurol. Sci.. 193. 63 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamaguchi,N. et al.: "Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations"Hum. Nutat.. 19. 122-130 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oshiro,S. et al.: "A patient with adult-onset type II citrullinemia on long-term hemodialysis: reversal of clinical symptoms and brain MRI findings"Am. J. Kidney Dis.. 39. 189-192 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Begum L. et al.: "Expression of three mitochondrial solute carriers, citrin, aralarl and ornithine transporter, in relation to urea cycle in mice"Biochim. Biophys. Acta. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Saheki,T. et al.: "Pathogenesis and pathophysiology of citrin )a mitochondrial aspartate glutamate carrier) deficiency"Metab. Brain Dis.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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