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Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans

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Abstract

Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1–3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (Iglll) domain in 50% (16/32) of our Crouzon syndrome patients2,4,5. All mutations described so far for other craniosynos-totic syndromes with associated limb anomalies — Jackson–Weiss2,4, Pfeiffer6–9, and Apert10,11 — also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions — achondroplasia12–14, thanatophoric dyspla-sia15,16, and hypochondroplasia17. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain12–14,18,19. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non–dwarfing and even non–skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. Our study underscores the biologic complexity of the FGFR gene family.

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References

  1. Reardon, W. et al. Mutations in the fibnoblast growth factor receptor 2 gene cause Crouzon syndrome. Nature Genet. 8, 98–103 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Jabs, E.W. et al. Jackson–Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nature Genet. 8, 275–279 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Gorry, M.C. et al. Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson–Weiss syndrome. Hum. molec. Genet. 4, 1387–1390 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Park, W.-J. et al. Novel FGFR2 mutations in Crouzon and Jackson–Weiss syndromes show allelic heterogeneity and phenotypic variability. Hum. molec. Genet. 4, 1229–1233 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Li, X., Park, W.-J., Pyeritz, R.E. & Jabs, E.W. Effect on splicing of a silent FGFR2 mutation in Crouzon syndrome. Nature Genet. 9, 232–233 (1995).

    Article  PubMed  Google Scholar 

  6. Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genet. 8, 269–274 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Rutland, P. et al. Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. Nature Genet. 9, 173–176 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Lajeunie, E., Ma, H.W., Bonaventure, J., Munnich, A. & Merrer, M.L. FGFR2 mutations in Pfeiffer syndrome. Nature Genet. 9, 108 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Schell, U. et al. Mutations in FGFR1 and FGFR2 cause both familial and sporadic Pfeiffer syndrome. Hum. molec. Genet. 4, 323–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Wilkie, A.O.M. et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nature Genet. 9, 165–172 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Park, W.-J. et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am. J. hum. Genet. 57, 321–328 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Shiang, R. et al. Mutations in the transmembrane domain of FGFRS cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Rousseau, F. et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252–254 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Supertifurga, A. et al. A glycine–375–to–cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor–3 in a newborn with achondroplasia. Eur. J. Ped. 154, 215–219 (1995).

    Article  CAS  Google Scholar 

  15. Tavormina, P.L. et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genet. 9, 321–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Rousseau, F. et al. Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nature Genet. 10, 11–12 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Bellus, G.A. et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nature Genet. 10, 357–359 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Bellus, G.A. et al. Achondroplasia is defined by recurrent G380R mutations of FGFRS. Am. J. hum. Genet. 56, 368–373 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Stoilov, I., Kilpatrick, M.W. & Tsipouras, P. A common FGFRS gene mutation is present in achondroplasia but not in hypochondroplasia. Am. J. med. Genet. 55, 127–133 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Rendon, M.I., Cruz, P.D. Jr, Sontneimer, R.D. & Bergstresser, P.R. Acanthosis nigricans: a cutaneous marker of tissue resistance to insulin. J. Am. Acad. Derm. 21, 461–469 (1989).

    Article  CAS  PubMed  Google Scholar 

  21. Orlow, S.J. Cutaneous findings in craniofacial malformation syndromes. Arch. Dermatol. 128, 1379–1386 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Breitbart, A.S., Eaton, C. & McCarthy, J.G. Crouzon's syndrome associated with acanthosis nigricans: ramifications for the craniofacial surgeon. Ann. Plastic Surg. 22, 310–315 (1989).

    Article  CAS  Google Scholar 

  23. Shi, D.L., Fromentoux, V, Launay, C., Umbhauer, M. & Boucaut, J.C. Isolation and developmental expression of the amphibian homolog of the fibroblast growth factor receptor 3. J. Cell Sci. 107, 417–425 (1994).

    CAS  PubMed  Google Scholar 

  24. Noji, S. et al. Differential expression of three chick FGF receptor genes, FGFR1, FGFR2, and FGFRS, in limb and feather development. Prog. clin. biol. Res. 638, 645–654 (1993).

    Google Scholar 

  25. Peters, K., Ornitz, D., Wemer, S. & Williams, L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev. Biol. 155, 423–430 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Murgue, B., Tsunekawa, S., Rosenberg, I., deBeaumont, M. & Podolsky, O.K. Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFRS Illb) in human colonic epithelium. Cancer Res. 54, 5206–5211 (1994).

    CAS  PubMed  Google Scholar 

  27. Partanen, J. et al. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO 10, 1347–1354 (1991).

    Article  CAS  Google Scholar 

  28. Chellaiah, A.T., McEwen, D.G., Werner, S., Xu, J. & Ornitz, D.M. Fibroblast growth factor receptor (FGFR) 3. J. biol. Chem. 269, 11620–11627 (1994).

    CAS  PubMed  Google Scholar 

  29. Avivi, A., Yayon, A. & Givol, D. A novel form of FGF receptor–3 using an alternative exon in the immunoglobulin domain III. FEBS Lett. 330, 249–252 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Ullrich, A. & Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Departments of Pediatrics, Medicine and Surgery, Center for Medical Genetics, The Johns Hopkins School of Medicine, 600 N. Wolfe Street, Baltimore, Maryland, 21287–3914, USA

    Gregory A. Meyers, Kelly A. Przylepa & Ethylin Wang Jabs

  2. The Ronald O. Perelman Department of Dermatology, Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA

    Seth J. Orlow

  3. Craniofacial Center at the Center for Children, Medical City Dallas Hospital, Dallas, Texas, 75230, USA

    Ian R. Munro

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  1. Gregory A. Meyers
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  2. Seth J. Orlow
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  3. Ian R. Munro
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  4. Kelly A. Przylepa
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  5. Ethylin Wang Jabs
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Meyers, G., Orlow, S., Munro, I. et al. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 11, 462–464 (1995). https://doi.org/10.1038/ng1295-462

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  • DOI: https://doi.org/10.1038/ng1295-462

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