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Systematic gene analysis for bone metabolism associated to TGF-β1

Research Project

Project/Area Number 13670147
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

YOSHIURA Koh-ichiro  Nagasaki University School of Medicine, Depart of Human Genetics Assistant Professor, 医学部, 助手 (00304931)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsCamurati-Engelmann disease / LAP / model mouse / infertility / Association study / LRP / Camurati-Engelmann発症群 / 相関解析 / Camurati-Engelmann病 / ジーンターゲッティング / キメラマウス / germline transmission / ES細胞 / エクソン4
Research Abstract

We analyzed 13 Camurati-Engelmann disease families for mutation in TGF-β1. We found four kinds of mutations, R218C, R218H, C223R, and C223G. These four mutations could occur nine times independently by judging from haplotype analysis around TGFB1 gene in Camurati-Engelmann disease families. This fact indicates mutations in Camurati-Engelmann disease are not transmitted from founder, but are fresh mutations occurred independently (paper submitted). We characterized the biochemical alterations of mutated TGF-β1 protein by transfection-expresssion assay system. In mutated proteins LAP (latency associated polypeptides) cannot associate to active TGF-β1, nor fold TGF-β1 to inactivate. This LAP dysfunction could cause the constitutive activation of TGF-b1 signal transduction in vivo. To search the bone metabolism in detail in vivo, we started to make knock-in mouse having R213C found in CED patient. Nine chimera mice were generated, but all of them were infertile because of immobility of sperm collected from epididymis. The cause of sperm immobility is not clear. There are two possibilities, ES cell itself might be damaged and TGF-b1 alteration might cause spermatogenesis. We screened 3 new homologous recombinant ES clones to make new knock-in mice.
Our mutation search in Camurati-Engelmann disease indicates that TGF-β1 regulate the bone metabolism. We search the SNPs (single nucleotide polymorphisms) in the TGF-β1, TGFB receptors, SMADs, LRP, and c-Fos genes. We performed association study using these SNPs and bone density in 500 Japanese. Association result shows that one polymorphism in LRP gene is the determinant for bone density (p-value < 0.03) (paper in preparation).

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Watanabe Y, et al.: "A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of Variations in genes for transforming growth factor-beta1 (TGF-beta1) and its signaling pathway"Journal of Human Genetics. 47. 478-483 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Saito, et al.: "Domain-specific mutations of a transforming growth (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1"Journal of Biological Chemistry. 276. 11469-11472 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kurotaki, et al.: "Haploinsufficiency of NSD1 causes Sotos Syndrome"Nature Genetics. 30. 365-366 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Saito T, Kinoshita A, Yoshiura K, Makita V, Wakui K, Honke K, Niikawa N, Taniguchi N: "Domain-specific mutations of a transforming growth factor (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1"Journal of Biological Chemistry. 276. 11469-11472 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Watanabe Y, Kinoshita A, Yamada T, Ohta T, Kishino T, Matsumoto N, Ishikawa M, Niikawa N, Yoshiura K: "A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-betal (TGF-betal) and its signaling pathway"Journal of Human Genetics. 47. 478-483 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y, Sugimoto T, Sonoda T, Hasegaea T, Chinen Y, Tomita H-a, Muzuguchi T, Yoshiura K-I, Ohta T, Kishino T, Fukushima Y, Niikawa N, Matsumoto N: "Haploinsufficiency of NSD1 causes Sotos syndrome"Nature Genet. 30. 365-366 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Watanabe Y, et al.: "A catalog of 106 single-nucleotide polymorphisms (SNPs) and 11 other types of variations in genes for transforming growth factor-beta1 (TGF-beta1) and its signaling pathway"Journal of Human Genetics. 47. 478-483 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Saito T, et al.: "Domain-specific Mutations of a Transforming Growth Factor (TGF)-beta 1 Latency-associated Peptide Cause Camurati-Engelmann Disease Because of the Formation of a Constitutively Active Form of TGF-beta 1"Journal of Biological Chemistry. 276. 11469-11472 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kurotani N, et al.: "Haploinsufficiency of NSD1 causes Sotos syndrome"Nature Genetics. 30. 365-366 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ghadami M, Yoshiura KI et al.: "Confirmation of genetic homogeneity of syndactyly type 1 in an Iranian family."American Journal of Medical Genetics. 104(2). 147-151 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kurotaki N, Yoshiura KI et al.: "Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene"Gene. 279(2). 197-204 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Saito T, Yoshiura KI et al.: "Domain-specific mutations of a transforming growth factor (TGF)-beta 1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-beta 1."Journal of Biological Chemistry. 276(15). 11469-114172 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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