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Genetic approach to Wilson disease by use of the hereditary hepatitis LEC rats

Research Project

Project/Area Number 03454499
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Human genetics
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

YOSHIDA Michihiro  Hokkaido Univ. ; Fac.Sci. ; Prof., 理学部, 教授 (60001765)

Co-Investigator(Kenkyū-buntansha) UMEHARA Chizuko  Hokkaido Univ. ; Fac.Sci. ; Research Assist., 理学部, 教務職員
増田 隆一  北海道大学, 理学部, 助手 (80192748)
ABE Shuichi  Hokkaido Univ. ; Fac.Sci. ; Assoc. Prof., 理学部, 助教授 (80125278)
Project Period (FY) 1991 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1993: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1992: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1991: ¥4,700,000 (Direct Cost: ¥4,700,000)
KeywordsWilson disease / LEC rats / Hapatitis / Liver cancer / Copper metabolism / Linkage / Ceruloplasmin / 連鎖 / ウィルソン病
Research Abstract

LEC rats develop abruptly about 4months after birth. Abot 30% of the rats die of fulminant hepatitis within 1 week, and remainder survive with chronic hepatitis and subsequently develop liver cancer. Recently, high levels of copper accumulation in the livers of LEC rats and gross reduction of serum ceruloplasmin have been found. These clinical and biochemical characteristics of LEC rats are very similar to Wilson disease, and therefore, we proposed the LEC as an animal model for Wilson disease. We defined hts as the gene symbol for the hepatitis. In this research project, we have examined whether the gene, WNE, for Wilson disease is homologous to the hts by use of backcross rats :
(1) Genetic analysis by use of backcross rats of LEC showed no linkage between hts and genes for ESD, RB1, and several minisatellite DNAs which linked to the WND in human, indicating that the hts locates on a different chromosome from no.15 on which RB1 and ESD are located.
(2) As gross reductin of serum ceruloplasmin was found in LEC rats, we have isolated the gene for ceruloplasmin from the LEC, and found no mutation in the gene of LEC, suggesting that the copper accumulatino is not due to alteration of the ceruloplasmin gene.
Linkage analysis of the hts and WND for Wilson disease showed the identical segregation pattern and no recombination demonstrating that the WND gene is a prime candidate for hts.
Thus, the results obtained here suggest that the hepatitis of LEC rats may be caused by a defect in a copper transporting ATPase, possibly due to mutation of hts.

Report

(4 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • 1991 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Sone,H.等: "Genetic linkage between copper accumulation and hepatitis/hepatoma development in LEC rats" Molec.Carcinogenesis. 5. 199-204 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ishida,A.,等: "Cloning and chromosome mapping of the human Mel-18 gene which encodes a DNA-binding protein with a new “RING-finger"motif" Gene. 129. 249-255 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Asano,H.,等: "The mouse Mel-18 “RING-finger" gene:genomic organization,promoter analysis and chromosomal assignment" DNA Sequence. 3. 369-377 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kagiyama,N.等: "A novel fluorescent method for in situ hybridization" Acta Histochem.Cytochem.26. 441-445 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ono,T.& Yoshida,M.C.: "Chromosomal assignment of retinoblastoma 1 gene(RB1)to mouse 14D3 and rat 15q12 by fluorescent in situ hybridization" Jpn.J.Genet.68. 617-621 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 吉田廸弘: "遺伝子解析から遺伝子治療へ" ライフサイエンス出版(関東肝臓集団会運営委員会編), 80 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ono T, Abe S, & Yoshida MC: "Hereditary low level of plasma ceruloplasmin in LEC rats associated with spontaneous development of hepatitis and liver cancer." Jpn J Cancer Res.8. 486-489 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sone H, Maeda M, Gotoh M, Wakabayashi K., Ono T, Yoshida MC, Takeichi N, Mori M, Hirohashi S, Sugimura T & Nagao M: "Genetic linkage between copper accumulation and hepatitis/hepatoma development in LEC rats." Molecular Carcinogenesis. 5. 199-204 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kasai N, Miyoshi I, Osanai T, Yamashita T, Kamimura E & Yoshida MC: "Effects of sex hormones on fulminant hepatitis in LEC rats : a model of Wioson's disease" Lab. Animal Sci.42 (4). 363-368 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ono T & Yoshida MC: "Chromosomal assignment of retinoblastoma gene (RB1) to mouse 14D3 and at 15q12 by fluorescent in situhybridization" Jpn J Genet. 68. 617-621 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yoshida MC SasakiM & Masuda R: Origin of the LEC strain with a new mutation causing hereditary hepatitis. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.3-10 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kasai N, Kamimura E, Miyoshi I & Yoshida MC: Reproductive performance and effects of pregnancy on the acute phase of hepatitis in LEC rats. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.11-19 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masuda R, Yoshida MC, Sasaki M Dempo K & Mori M: High susceptivility to spontaneous development of hepatocellular carcinoma in LEC rats. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.54-66 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ono T, Abe S & Yoshida MC: Hereditary low levels of plasma ceruloplasmin in LEC rats. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.133-141 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masuda R, Ono T, Yoshida MC, & Sasaki M: Chromosomal analysis of spontaneous hepatomas, a derived cell line, and chemically induced hepatomas in LEC rats. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.244-260 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masuda R, Abe S, Yoshida MC, Sasaki M, Sugiyama T & Taniguchi N: Drug-metabolizing ability and inducibility of chromosomal aberrations and sister chromatid exchanges in LEc rats exposed to cyclophosphamide. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.328-334 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masuda R, Sugiyama T, Taniguchi N, Yoshida MC, & Sasaki M: Hepatomaassociated alterations of serum alpha-1-antitrypsin in LEC rats. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.328-344 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masuda R, Yoshida MC & Sasaki M: Chromosomal mapping of theplacental glutathione S-transferase gene and its expression in livers of LEC rats. In The LEC Rat (eds. M Mori, Yoshida MC, N Takeichi, & N Taniguchi). Springer-Verlag, Tokyo, pp.341-348 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sone,H.等: "Genetic linkage between copper accumuiation and hepatitis/hepatoma development in LEC rats" Molec.Carcinogenesis. 5. 199-204 (1992)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ishida,A.,等: "Cloning and chromosome mapping of the human Mel-18 gene which encodes a DNA-binding protein with a new "RING-finger"motif" Gene. 129. 249-255 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Asano,H.,等: "The mouse Mel-18 "RING-finger" gene: genomic organization,promoter analysis and chromosomal assignment" DNA Sequence. 3. 369-377 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Kagiyama,N.等: "A novel fluorescent method for in situ hybridization" Acta Histochem. Cytochem.26. 441-445 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ono,T. & Yoshida,M.C.: "Chromosomal assignment of retinoblastoma 1 gene (RB1) to mouse 14D3 and rat 15q12 by fluorescent in situ hybridization" Jpn.J.Genet.68. 617-621 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 吉田廸弘: "遺伝子解析から遺伝子治療へ" ライフサイエンス出版(関東肝臓集団会運営委員会編), 80 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] M.Hirashima,Ovo,T.Yoshida,M.C.: "Nucleotide sequence of the thivd cytokine LD78gene and mapping of all thiee LD78gene loci to human chromosome 17" DNA Sequence. 3. 203-212 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sone,H.… Yoshida,M.C.…: "Genetic linkage between copper accumulation and hepatitis/hepatoma developmeut in LECrats" Molecl.Carcinogenesis. 5. 199-204 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kasai,N.,… Yoshida,M.C.: "Efficts of sex hormones on fulninaut hepatitis in LECrats:Amodel of Wilson's disease." Lab.Anim.Sci.42. 363-368 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshida,M.C.: "Receut advances in fluoresceuce in situ hipraidization" J.RAdiat.Ras.Suppl.33. 54-60 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sofuni,T.and Yoshida,M.C.: "Conibined use of seve.ral mitogensfol mitotic stimulation to human lymphocytes" J.Radiat.Res.Suppl.33. 223-230 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 吉田 廸弘: "性染色体の進化" 小児内科. 24. 5-11 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 吉田 廸弘(村松正実編): "医科分子生物学" 南江堂, 479 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] 吉田 廸弘: "臨床遺伝医学III(古庄,外村,清水,北川編)" 診断と治療社, 643 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kato,S.,Tachibana,K.,Takayama,N,Kataoka,H.,Yoshida,M.C.& Takano,T.: "Genetic recombination in a chromosomal translocation t(2;8)(p11;q24)of a Burkitt's lymphoma cell line,KOBK101." Gene. 97. 239-244 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yoshida,M.C.,Nishizawa,M.,Kataoka,K.,Goto,N.,Fujiwara K.T.,& Kawai,S.: "Localization of the human MAF protooncogene on chromosome 16 to bands q22ーq23." Cytogenet.Cell Genet.58. 2003 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Matsuoka,R.,Yoshida,MC,Kanda,N.,Furutani,Y.,Bruns,G.Yanagisawa,M.& Takao,A.: "Human smooth muscle myosin heavyーchain gene mapped to chromosomal region 16q12.1ーql2.2." Cytogenet.Cell Genet.58. 2000-2001 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Ono,T.,Abe,S.,& Yoshida,MC: "Hereditary low level of plasma ceruloplasmin in LEC rats associated with spontaneous development of hepatitis and liver cancer" Jpn.J.Cancer Res.82. 486-489 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Arinami,T,Ishikawa,M,Inoue A,Yanagisawa,M,Masaki,T,Yoshida,MC,& Hamaguchi,H: "Chromosomal assignments of the human endothelin family genes:the endothelinー1 gene(EDN1)to 6p23ーp24,the endothelinー2(EDN2) gene to 1p34,and the endothelinー3(EDN3)gene to20q13.2ーq13.3" Am.J.Hum.Genet.48. 990-996 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Ozawa,K,Sudo,T.Soeda,E.,Yoshida,MC,&Ishii,S.: "Assignment of the human CREB2(CRE BP1)gene to 2q32" Genomics. 10. 1103-1104 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Mori,M.,Yoshida,M.C.,Takeichi,N.,& Taniguchi,N.(Eds.): "The LEC Rat" SpringerーVerlag, 356 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 村松 正実(編): "医科分子生物学" 南江堂, 479 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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