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.

  • Article
  • Published:

Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome

Nature Genetics volume 8, pages 98–103 (1994)Cite this article

Abstract

Crouzon syndrome is an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis) and maps to chromosome 10q25–q26. We now present evidence that mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome. We found SSCP variations in the B exon of FGFR2 in nine unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in three unrelated multigenerational families. In four sporadic cases, the normal parents did not have SSCP variation. Finally, direct sequencing has revealed specific mutations in the B exon in all nine sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in five patients.

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
Buy now

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

Similar content being viewed by others

References

  1. Cohen, M.M.Jr, Craniosynostosis: diagnosis, evaluation and management. (Raven Press, New York, 1986).

  2. Winter, R.M. & Baraitser, M. The London Dysmorphology Database. (Oxford University Press, Oxford, 1994).

  3. Warman, M.L., Mulliken, J.B., Hayward, P.G. & Muller, U. Newly recognised autosomal dominant craniosynostotic syndrome. Am. J. med. Genet. 46, 444–449 (1993).

    Article  CAS  Google Scholar 

  4. Muller, U., Warman, M.L., Mulliken, J.B. & Weber, J. Assignment of a gene locus Involved in craniosynostosis to chromosome 5qter. Hum. molec. Genet. 2, 119–122 (1992).

    Article  Google Scholar 

  5. Jabs, E.W. et al. Mutation in the Homeodomain of the Human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Cell 75, 443–450 (1993).

    Article  CAS  Google Scholar 

  6. Brueton, L.A., van Herwerden, L., Chotai, K.A. & Winter, R.M. The mapping of a gene for craniosynostosis: evidence for linkage of the Saethre-Chotzen syndrome to distal chromosome 7p. J. med. Genet. 29, 681–685 (1992).

    Article  CAS  Google Scholar 

  7. van Herwerden, L. et al. Evidence for locus heterogeneity in acrocephalosyndactyly: a refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p — and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p & 5q. Am. J. hum. Genet. 54, 669–674 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lewanda, A.F. et al. Genetic Heterogeneity among craniosynostosis syndromes: mapping the Saethre-Chotzen syndrome locus between D7S513 & D7S516 and exclusion of Jackson-Weiss & Crouzon syndrome loci from 7p. Genomics 19, 115–119 (1994).

    Article  CAS  Google Scholar 

  9. Reardon, W., McManus, S.P., Summers, D. & Winter, R.M. Cytogenetic evidence that the Saethre-Chotzen gene maps to 7p21.2. Am. J. med. Genet. 47, 633–636 (1993).

    Article  CAS  Google Scholar 

  10. Reid, C.S. et al. Saethre-Chotzen syndrome with familial translocation at chromosome 7p22. Am. J. med. Genet. 47, 637–639 (1993).

    Article  CAS  Google Scholar 

  11. Reardon, W., van Herwerden, L., Rose, C., Jones, B., Malcolm, S. & Winter, R.M. Crouzon syndrome is not linked to craniosynostosis loci at 7p & 5qter. J. med. Genet. 31, 219–221 (1994).

    Article  CAS  Google Scholar 

  12. Preston, R.A. et al. A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10. Nature Genet. 7, 149–153 (1994).

    Article  CAS  Google Scholar 

  13. Johnson, D.E., Lee, P.L., Lu, J. & Williams, L.T. Diverse forms of a receptor for acidic & basic fibroblast growth factors. Molec. Cell. Genet. 10, 4728–4736 (1990).

    CAS  Google Scholar 

  14. Kombluth, S., Paulson, K.E. & Hanafusa, H. Novel Tyrosine Kinase identified by Phosphotyrosine antibody screening of cDNA libraries. Molec. Cell. Biol. 8, 5541–5544 (1988).

    Article  Google Scholar 

  15. Lee, P.L., Johnson, D.E., Cousens, L.S., Fried, V.A. & Williams, L.T. Purification and complementary DNA sequence of areceptor for basic Fibroblast Growth Factor. Science 245, 57–60 (1989).

    Article  CAS  Google Scholar 

  16. Ruta, M. et al. Receptor for acidic fibroblast growth factor is related to the tyrosine klnase encoded by the fms-like gene (FLG). Proc. natn. Acad. Sci. U.S.A. 86, 8722–8726 (1989).

    Article  CAS  Google Scholar 

  17. Reid, H.H., Wilks, A.F. & Bernard, O. Two forms of basic fibroblast growth factor receptor-like mRNA are expressed in the developing mouse brain. Proc. natn. Acad. Sci. U.S.A 87, 1596–1600 (1990).

    Article  CAS  Google Scholar 

  18. Mansukhani, A., Moscatelli, D., Talarico, D., Levytska, V. & Basilico, C. A murine fibroblast growth factor (FGF) receptor expressed in CHO Cells is activated by basis FGF & Kaposi FGF. Pro. natn. Acad. Sci. U.S.A. 87, 4378–4382 (1990).

    Article  CAS  Google Scholar 

  19. Dionne, C.A. et al. Cloning & expression of two distinct high-affinity receptors cross-reacting with acidic & basic fibroblast growth factors. EMBO J. 8, 2685–2692 (1990).

    Article  Google Scholar 

  20. Houssaint, E. et al. Related fibroblast growth factor receptor genes exist in the human genome. Proc. natn. Acad. Sci. U.S.A. 87, 8180–8184 (1990).

    Article  CAS  Google Scholar 

  21. Pasquale, E.B. A distinctive family of embryonic protein-tyroslne kinase receptors. Proc. natn. Acad. Sci. U.S.A. 87, 5812–5816 (1990).

    Article  CAS  Google Scholar 

  22. Raz, V., Keiman, Z., Avivi, A., Neufeld, G., Givol, D. & Yarden, Y. PCR-Based identification of new receptors — molecular cloning of a receptor for Fibroblast growth factors. Oncogens 6, 753–760 (1991).

    CAS  Google Scholar 

  23. Keegan, K., Johnson, D.E., Williams, L.T. & Hayman, M.J. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3. Proc. natn. Acad. Sci. U.S.A 88, 1095–1099 (1993).

    Article  Google Scholar 

  24. Partanen, J. et al. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 1347–1354 (1991).

    Article  CAS  Google Scholar 

  25. Johnson, D.E., Lu, J., Chen, H., Werner, S. & Williams, L.T. The Human Fibroblast Growth Factor Genes: acommon structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Molec. Cell. Biol. 11, 4627–4634 (1991).

    Article  CAS  Google Scholar 

  26. Miki, T. et al. Determination of ligand-binding specificity by alternative splicing: Two distinct growth factor receptors encoded by a single gene. Proc. natn. Acad. Sci. U.S.A. 89, 246–250 (1992).

    Article  CAS  Google Scholar 

  27. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarflsm, Achondroplasia. Cell 78, 335–342 (1994).

    Article  CAS  Google Scholar 

  28. Mattei, M-G., Moreau, A., Gesnel, M-C., Houssaint, E. & Breathnach, R. Assignment by in situ hybridization of a fibroblast growth factor receptor gene to human chromosome band 10q26. Hum. Genet. 87, 84–86 (1991).

    Article  CAS  Google Scholar 

  29. Dionne, C.A., Modi, W.S., Crumley, G., O'Brien, S.J., Schlessinger, J. & Jaye, M. BEK, a receptor for multiple members of the fibroblast growth factor (FGF) family, maps to human chromosome 10q25.3–q26. Cytogenet Cell Genet. 60, 34–36 (1992).

    Article  CAS  Google Scholar 

  30. Gilbert, E., Del Gatto, F., Champion-Amaud, P., Gesnel, M-C. & Breathnach, R. Control of Bek and K-Sam splice sites in alternative splicing of the fibroblast growth factor receptor 2 pre-mRNA. Molec. Cell. Biol. 13, 5461–5468 (1993).

    Article  CAS  Google Scholar 

  31. Orr-Uretreger, A. et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR-2). Devel. Biol. 158, 475–486 (1993).

    Article  Google Scholar 

  32. Orr-Uretreger, A., Givol, D., Yayon, A., & Lonai, P. Developmental expression of two murine fibroblast growth factor receptors, fig & bek. Development 113, 1419–1434 (1991).

    Google Scholar 

  33. Shapiro, M.B. & Senepathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics & fundamental implication in gene expression. Nucl. Acids Res. 15, 7155–7174 (1987).

    Article  CAS  Google Scholar 

  34. Langer, L.O. et al. Thanatophoric Dysplasia & Cloverteaf Skull. Am. J. med. Genet. Suppl. 3, 167–179 (1987).

    Article  Google Scholar 

  35. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl. Acids Res. 16, 1215 (1988).

    Article  CAS  Google Scholar 

  36. Orita, M., Iwahana, H., Kanazawa, M., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single strand conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1987).

    Article  Google Scholar 

  37. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis In human. Proc. natn. Acad. Sci. U.S.A 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mothercare Unit of Clinical Genetics and Fetal Medicine and Molecular Genetics Unit, Institute of Child Health, 30 Guilford St., London, WC1N 1EH, UK

    Robin M. Winter, Paul Rutland, Louise J. Pulleyn & Sue Malcolm

  2. Dept of Plastic and Reconstructive Surgery, Great Ormond St. Hospital For Children, London, WC1N 3JN, UK

    Barry M. Jones

Authors
  1. William Reardon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin M. Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Rutland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Louise J. Pulleyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barry M. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sue Malcolm
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reardon, W., Winter, R., Rutland, P. et al. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8, 98–103 (1994). https://doi.org/10.1038/ng0994-98

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0994-98

This article is cited by

Search

Advanced 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