Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A human chondrodysplasia due to a mutation in a TGF-β superfamily member

Abstract

The TGF-β superfamily comprises a number of functionally diverse growth factors/signalling molecules1 which elicit their response upon binding to serine-threonine kinase receptors2. We recently reported the isolation and characterization of two new members of the family, designated cartilage-derived morphogenetic protein (CDMP) 1 and 2 (ref.3) which are closely related to the sub-family of bone morphogenetic proteins. CDMP-1 is predominantly expressed at sites of skeletal morphogenesis3, and we now show that a mutation in hCDMP-1 is associated with a recessive human chondrodysplasia (acromesomelic chondrodysplasia, Hunter-Thompson type4,5). The disorder, characterized by skeletal abnormalities restricted to the limbs and limb joints, is phenotypically similar to murine brachypodism (bp) which is due to mutations in growth/differentiation factor-5 (Gdf-5)6, the mouse homologue of hCDMP-1. Affected individuals are homozygous for a 22-bp (tandem-duplication) frameshift mutation in the mature region of CDMP-1. The resulting phenotype provides direct evidence for the involvement of CDMP-1 in human skeletal development and represents the first human disorder attributable to a mutation in a TGF-β superfamily member.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kingsley, D.M. What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet. 10, 16–21 (1994).

    Article  CAS  Google Scholar 

  2. Massagué, J., Attisano, L. & Wrana, J.L., TGF-β family and its composite receptors. Trends Cell. Biol. 4, 172–178 (1994).

    Article  Google Scholar 

  3. Chang, S.C. et al. Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-β superfamily predominantly expressed in long bones during human embryonic development. J. Biol. Chem. 269, 28227–28234 (1994).

    CAS  PubMed  Google Scholar 

  4. Hunter, A.G.W. & Thompson, M.W. Acromesomelic dwarfism: description of a patient and comparison with previously reported cases. Hum. Genet. 34, 107–113 (1976).

    Article  CAS  Google Scholar 

  5. Langer, L.O., Cervenka, J. & Camargo, M. A severe autosomal recessive acromesomelic dysplasia, the Hunter-Thompson type, and comparison with the Grebe type. Hum. Genet. 81, 323–328 (1989).

    Article  Google Scholar 

  6. Storm, E.E. et al. Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ superfamily. Nature 368, 639–643 (1994).

    Article  CAS  Google Scholar 

  7. Urist, M.R. Bone: formation by autoinduction. Science 159, 893–899 (1965).

    Article  Google Scholar 

  8. Celeste, A.J. et al. Identification of transforming growth factor β family members present in bone-inductive protein purified from bovine bone. Proc. Natl. Acad. Sci. USA 87, 9843–9847 (1990).

    Article  CAS  Google Scholar 

  9. Luyten, F.P. et al. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation. J. Biol. Chem. 264, 13377–13380 (1989).

    CAS  PubMed  Google Scholar 

  10. Özkaynak, E. et al. OP-1 cDNA encodes an osteogenic protein in the TGF–beta family. EMBO J. 9, 2085–2093 (1990).

    Article  Google Scholar 

  11. Sampath, T.K., Muthukumaran, N. & Reddi, A.H. Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. Proc. Natl. Acad. Sci. USA 84, 7109–7113 (1987).

    Article  CAS  Google Scholar 

  12. Wang, E.A. et al. Purification and characterization of other distinct bone-inducing factors. Proc. Natl. Acad. Sci. USA 85, 9484–9488 (1988).

    Article  CAS  Google Scholar 

  13. Wozney, J.M. et al. Novel regulators of bone formation: molecular clones and activities. Science 242, 1528–1534 (1988).

    Article  CAS  Google Scholar 

  14. Padgett, R.W., St. Johnston, D. & Gelbart, W.M. A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-beta family. Nature 325, 81–84 (1987).

    Article  CAS  Google Scholar 

  15. Wharton, K.A., Thomsen, G.H. & Gelbart, W.M. Drosophila 60A gene, another transforming growth factor β family member, is closely related to human bone morphogenetic proteins. Proc. Natl. Acad. Sci. USA 88, 9214–9218 (1991).

    Article  CAS  Google Scholar 

  16. Stenzel, P., Angerer, L.M., Smith, B.J., Angerer, R.C. & Vale, W.W. The univin gene encodes a member of the transforming groth factor-β superfamily with restricted expression in the sea urchin embryo. Develop. Biol. 166, 149–158 (1994).

    Article  CAS  Google Scholar 

  17. Kingsley, D.M. et al. The mouse short ear skeletal morphogenesis locus is associatedwith defects in a bone morphogenetic member of the TGF beta superfamily. Cell 71, 399–410 (1992).

    Article  CAS  Google Scholar 

  18. Spanger, J. International classification of osteochondrodysplasias. Eur. J. Padiatr 151, 407–415 (1992).

    Article  Google Scholar 

  19. McKusick, V.A. in Mendelian Inheitance in Man: A Catalogue of Human Genes and Genetic Disorders (ed. McKusick, V.A.) (The Johns Hopkins University Press, Baltimore and London, 1994).

    Google Scholar 

  20. Grüneberg, H. & Lee, A.J. The anatomy and development of brachypodism in the mouse. J. Embryol. Exp. Morph. 30, 119–141 (1973).

    PubMed  Google Scholar 

  21. Venkataraman, G., Sasisekharan, V., Cooney, C.L., Langer, R. & Sasisekharan, R. Complex flexibility of the transforming growth factor β superfamily. Proc. Natl. Acad. Sci. USA 92, 5406–5410 (1995).

    Article  CAS  Google Scholar 

  22. Griffith, D.L., Keck, P., Sampath, T.K., Rueger, D.C. & Carison, W.D. Three dimensional structure of recombinant human osteogenic protein 1: Structural paradigm for transforming growth factor β superfamily proteins. Proc. Natl. Acad. Sci. USA (in the press).

  23. Amatayakul-Chantler, S. et al. [Ser77] transforming growth factor-β1. Selective biological activity and receptor binding in mink lung epithelial cells. J. Biol. Chem. 269, 27687–27691 (1994).

    CAS  PubMed  Google Scholar 

  24. Brunner, A.M. et al. Site-directed mutagenesis of glycosylation sites in the transforming growth factor-β1 (TGFβ1) and TGFβ2 (414) precursors and of cysteine residues within TGFβ1: effects on secretion and bioactivity. Molec. Endocrinol. 6, 1691–1700 (1992).

    CAS  Google Scholar 

  25. Walsh, P.S., Metzger, D.A. & Higuchi, R. Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques 10, 506–513 (1991).

    CAS  PubMed  Google Scholar 

  26. Greulich, W.W. & Pyle, S.I. in Radiographic Atlas of Skeletal Development of the Hand and Wrist (eds Greulich, W.W. & Pyle, S.I.) 108–109 (Stanford University Press, Stanford, CA, 1983).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thomas, J., Lin, K., Nandedkar, M. et al. A human chondrodysplasia due to a mutation in a TGF-β superfamily member. Nat Genet 12, 315–317 (1996). https://doi.org/10.1038/ng0396-315

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0396-315

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing