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.

Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia

Abstract

ACHONDROPLASIA, the most common cause of chondrodysplasia in man (1 in 15,000 live births), is a condition of unknown origin characterized by short-limbed dwarfism and macrocephaly1,2. More than 90% of cases are sporadic and there is an increased paternal age at the time of conception of affected individuals, suggesting that de novo mutations are of paternal origin. Affected individuals are fertile and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, accounting for rare familial forms of the disease (l0%))3–6. In contrast, homozygous achondroplasia is usually lethal in the neonatal period and affects 25% of the offspring of matings between heterozygous achondroplasia parents. The gene responsible for achondroplasia has been mapped to chromosome 4pl6.3 (refs 7, 8); the genetic interval encompassing the disease gene contains a member of the fibroblast-growth-factor receptor (FGFR3) family which is expressed in articular chondrocytes. Here we report the finding of recurrent missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic cases and 6 unrelated familial forms of achondroplasia. We show that the mutant genotype segregates with the disease in these families. Thus it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Maroteaux, P. & Lamy, M. Clin. Orthop. 33, 91–103 (1964).

    Article  CAS  Google Scholar 

  2. Oberklaid, F., Danks, D. M., Jensen, F., Stace, I. & Rosshandler, S. J. med. Genet. 16, 140–146 (1979).

    Article  CAS  Google Scholar 

  3. Murdoch, J. L. et al. Ann. hum. Genet. 33, 227–244 (1970).

    Article  CAS  Google Scholar 

  4. Orioli, I. M., Castilla, E. E. & Barbosa-Neto, J. G. J. med. Genet. 23, 328–332 (1986).

    Article  CAS  Google Scholar 

  5. Stoll, C., Dott, B., Roth, M. P. & Alembik, Y. Clin. Genet. 35, 88–92 (1989).

    Article  CAS  Google Scholar 

  6. Gardner, R. J. M. Clin. Genet. 11, 31–38 (1977).

    Article  CAS  Google Scholar 

  7. Le Merrer, M. et al. Nature Genet. 6, 318–321 (1994).

    Article  CAS  Google Scholar 

  8. Velinov, M. et al. Nature Genet. 6, 314–317 (1994).

    Article  CAS  Google Scholar 

  9. Stanescu, R., Stanescu, V. & Maroteaux, P. Am. J. med. Genet. 37, 412–421 (1990).

    Article  CAS  Google Scholar 

  10. Thompson, L. et al. Genomics 11, 1133–1142 (1991).

    Article  CAS  Google Scholar 

  11. Ullrich, A. & Schlessinger, J. Cell 61, 203–212 (1990).

    Article  CAS  Google Scholar 

  12. Keegan, K., Johnson, D., Williams, L. T. & Hayman, M. J. Proc. natn. Acad. Sci. U.S.A. 88, 1095–1099 (1991).

    Article  ADS  CAS  Google Scholar 

  13. Kato, Y. & Iwamoto, M. J. biol. Chem. 265, 5903–5909 (1990).

    CAS  PubMed  Google Scholar 

  14. Iwamoto, M., Shimazu, A., Nakashima, K., Suzuki, F. & Kato, Y. J. biol. Chem. 266, 461–467 (1991).

    CAS  PubMed  Google Scholar 

  15. Ornitz, D. M. & Leder, P. J. biol. Chem. 267, 16305–16311 (1992).

    CAS  PubMed  Google Scholar 

  16. Pasquale, E. B. Proc. natn. Acad. Sci. U.S.A. 87, 5812–5816 (1990).

    Article  ADS  CAS  Google Scholar 

  17. Williams, L. T. Science 243, 1564–1570 (1989).

    Article  ADS  CAS  Google Scholar 

  18. Edery, P. et al. Nature 367, 378–380 (1994).

    Article  ADS  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rousseau, F., Bonaventure, J., Legeai-Mallet, L. et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252–254 (1994). https://doi.org/10.1038/371252a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/371252a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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