title: An ENU-induced p.C225S missense mutation in the mouse Tgfb1 gene does not cause Camurati-Engelmann disease-like skeletal phenotypes.
abstract: Camurati-Engelmann disease (CED) is a rare sclerosing bone disorder in humans with autosomal dominant inheritance. Mutations in the gene (TGFB1) 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 Tgfb1 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.
authors.affiliation: 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.
authors.forename: Satoki
authors.initials: S
authors.lastname: Ichimura
authors.affiliation: 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.
authors.forename: Shun
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Murata
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukumura
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.affiliation: 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.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D003966:Camurati-Engelmann Syndrome / Q000235:genetics*; D003545:Cysteine; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D015723:Gene Library; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense / Q000187:drug effects; D010641:Phenotype; D012694:Serine; D015398:Signal Transduction / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D012694:Serine; D003545:Cysteine; D005038:Ethylnitrosourea
keywords: Camurati-Engelmann disease; ENU-mutagenized mice; TGF-β1