An ENU-induced p.C225S missense mutation in the mouse <i>Tgfb1</i> gene does not cause Camurati-Engelmann disease-like skeletal phenotypes

Access this Article

Author(s)

    • ICHIMURA Satoki ICHIMURA Satoki
    • Laboratory of Laboratory Animal Science and Medicine, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan
    • SASAKI Shun SASAKI Shun
    • Laboratory of Laboratory Animal Science and Medicine, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan
    • IKEGAWA Shiro IKEGAWA Shiro
    • Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
    • FURUICHI Tatsuya FURUICHI Tatsuya
    • Laboratory of Laboratory Animal Science and Medicine, Co-Department of Veterinary Medicine, Faculty of Agriculture, Iwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan

Abstract

<p>Camurati-Engelmann disease (CED) is a rare sclerosing bone disorder in humans with autosomal dominant inheritance. Mutations in the gene (<i>TGFB1</i>) that encodes transforming growth factor-β1 (TGF-β1) are causative for CED. TGF-β1 signaling is enhanced by the CED-causing mutations. In this study, we performed <i>Tgfb1</i> mutation screening in an ENU-mutagenized mouse genomic DNA library. We identified a missense mutation in which cysteine was substituted by serine at position 225 (p.C225S), that corresponded to the CED-causing mutation (p.C225R). TGF-β1 mutant protein carrying p.C225S was secreted normally into the extracellular space. Reporter gene assays showed that the p.C225S mutants enhanced TGF-β signaling at the same level as p.C225R mutants. We generated p.C225S homozygous mice and confirmed that the mature TGF-β1 levels in the culture supernatants of the calvarial cells from the homozygotes were significantly higher than those from wild-type mice. Although the skull and femur are sclerotic in CED, these phenotypes were not observed in p.C225S homozygous mice. These results suggest that human and mouse bone tissue react differently to TGF-β1. These findings are useful to pharmacological studies using mouse models in developing drugs that will target TGF-β signaling.</p>

Journal

  • Experimental Animals

    Experimental Animals 66(2), 137-144, 2017

    Japanese Association for Laboratory Animal Science

Codes

  • NII Article ID (NAID)
    130005635560
  • NII NACSIS-CAT ID (NCID)
    AA11032321
  • Text Lang
    ENG
  • ISSN
    1341-1357
  • NDL Article ID
    028109945
  • NDL Call No.
    Z54-H752
  • Data Source
    NDL  J-STAGE 
Page Top