Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Mar;64(3):722–731. doi: 10.1086/302275

A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.

P L Tavormina 1, G A Bellus 1, M K Webster 1, M J Bamshad 1, A E Fraley 1, I McIntosh 1, J Szabo 1, W Jiang 1, E W Jabs 1, W R Wilcox 1, J J Wasmuth 1, D J Donoghue 1, L M Thompson 1, C A Francomano 1
PMCID: PMC1377789  PMID: 10053006

Abstract

We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations.

Full Text

The Full Text of this article is available as a PDF (582.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baker K. M., Olson D. S., Harding C. O., Pauli R. M. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet. 1997 Jun 27;70(4):427–436. [PubMed] [Google Scholar]
  2. Basilico C., Moscatelli D. The FGF family of growth factors and oncogenes. Adv Cancer Res. 1992;59:115–165. doi: 10.1016/s0065-230x(08)60305-x. [DOI] [PubMed] [Google Scholar]
  3. Bellus G. A., Gaudenz K., Zackai E. H., Clarke L. A., Szabo J., Francomano C. A., Muenke M. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet. 1996 Oct;14(2):174–176. doi: 10.1038/ng1096-174. [DOI] [PubMed] [Google Scholar]
  4. Bellus G. A., Hefferon T. W., Ortiz de Luna R. I., Hecht J. T., Horton W. A., Machado M., Kaitila I., McIntosh I., Francomano C. A. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet. 1995 Feb;56(2):368–373. [PMC free article] [PubMed] [Google Scholar]
  5. Bellus G. A., McIntosh I., Smith E. A., Aylsworth A. S., Kaitila I., Horton W. A., Greenhaw G. A., Hecht J. T., Francomano C. A. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995 Jul;10(3):357–359. doi: 10.1038/ng0795-357. [DOI] [PubMed] [Google Scholar]
  6. Bellus G. A., McIntosh I., Szabo J., Aylsworth A., Kaitila I., Francomano C. A. Hypochondroplasia: molecular analysis of the fibroblast growth factor receptor 3 gene. Ann N Y Acad Sci. 1996 Jun 8;785:182–187. doi: 10.1111/j.1749-6632.1996.tb56257.x. [DOI] [PubMed] [Google Scholar]
  7. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Colvin J. S., Bohne B. A., Harding G. W., McEwen D. G., Ornitz D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996 Apr;12(4):390–397. doi: 10.1038/ng0496-390. [DOI] [PubMed] [Google Scholar]
  9. Deng C., Wynshaw-Boris A., Zhou F., Kuo A., Leder P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell. 1996 Mar 22;84(6):911–921. doi: 10.1016/s0092-8674(00)81069-7. [DOI] [PubMed] [Google Scholar]
  10. Ho K. L., Chang C. H., Yang S. S., Chason J. L. Neuropathologic findings in thanatophoric dysplasia. Acta Neuropathol. 1984;63(3):218–228. doi: 10.1007/BF00685248. [DOI] [PubMed] [Google Scholar]
  11. Johnson D. E., Williams L. T. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41. doi: 10.1016/s0065-230x(08)60821-0. [DOI] [PubMed] [Google Scholar]
  12. Langer L. O., Jr, Yang S. S., Hall J. G., Sommer A., Kottamasu S. R., Golabi M., Krassikoff N. Thanatophoric dysplasia and cloverleaf skull. Am J Med Genet Suppl. 1987;3:167–179. doi: 10.1002/ajmg.1320280521. [DOI] [PubMed] [Google Scholar]
  13. MacDonald I. M., Hunter A. G., MacLeod P. M., MacMurray S. B. Growth and development in thanatophoric dysplasia. Am J Med Genet. 1989 Aug;33(4):508–512. doi: 10.1002/ajmg.1320330420. [DOI] [PubMed] [Google Scholar]
  14. McKusick V. A., Kelly T. E., Dorst J. P. Observations suggesting allelism of the achondroplasia and hypochondroplasia genes. J Med Genet. 1973 Mar;10(1):11–16. doi: 10.1136/jmg.10.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Meyers G. A., Orlow S. J., Munro I. R., Przylepa K. A., Jabs E. W. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet. 1995 Dec;11(4):462–464. doi: 10.1038/ng1295-462. [DOI] [PubMed] [Google Scholar]
  16. Mohammadi M., Dikic I., Sorokin A., Burgess W. H., Jaye M., Schlessinger J. Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction. Mol Cell Biol. 1996 Mar;16(3):977–989. doi: 10.1128/mcb.16.3.977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mohammadi M., Schlessinger J., Hubbard S. R. Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism. Cell. 1996 Aug 23;86(4):577–587. doi: 10.1016/s0092-8674(00)80131-2. [DOI] [PubMed] [Google Scholar]
  18. Muenke M., Gripp K. W., McDonald-McGinn D. M., Gaudenz K., Whitaker L. A., Bartlett S. P., Markowitz R. I., Robin N. H., Nwokoro N., Mulvihill J. J. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997 Mar;60(3):555–564. [PMC free article] [PubMed] [Google Scholar]
  19. Naski M. C., Wang Q., Xu J., Ornitz D. M. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996 Jun;13(2):233–237. doi: 10.1038/ng0696-233. [DOI] [PubMed] [Google Scholar]
  20. Neilson K. M., Friesel R. Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains. J Biol Chem. 1996 Oct 4;271(40):25049–25057. doi: 10.1074/jbc.271.40.25049. [DOI] [PubMed] [Google Scholar]
  21. Nishimura G., Fukushima Y., Ohashi H., Ikegawa S. Atypical radiological findings in achondroplasia with uncommon mutation of the fibroblast growth factor receptor-3 (FGFR-3) gene (Gly to Cys transition at codon 375) Am J Med Genet. 1995 Nov 20;59(3):393–395. doi: 10.1002/ajmg.1320590325. [DOI] [PubMed] [Google Scholar]
  22. Norman A. M., Rimmer S., Landy S., Donnai D. Thanatophoric dysplasia of the straight-bone type (type 2). Clin Dysmorphol. 1992 Apr;1(2):115–120. [PubMed] [Google Scholar]
  23. Prinos P., Costa T., Sommer A., Kilpatrick M. W., Tsipouras P. A common FGFR3 gene mutation in hypochondroplasia. Hum Mol Genet. 1995 Nov;4(11):2097–2101. doi: 10.1093/hmg/4.11.2097. [DOI] [PubMed] [Google Scholar]
  24. Rousseau F., Bonaventure J., Legeai-Mallet L., Pelet A., Rozet J. M., Maroteaux P., Le Merrer M., Munnich A. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994 Sep 15;371(6494):252–254. doi: 10.1038/371252a0. [DOI] [PubMed] [Google Scholar]
  25. Rousseau F., Saugier P., Le Merrer M., Munnich A., Delezoide A. L., Maroteaux P., Bonaventure J., Narcy F., Sanak M. Stop codon FGFR3 mutations in thanatophoric dwarfism type 1. Nat Genet. 1995 May;10(1):11–12. doi: 10.1038/ng0595-11. [DOI] [PubMed] [Google Scholar]
  26. Rousseau F., el Ghouzzi V., Delezoide A. L., Legeai-Mallet L., Le Merrer M., Munnich A., Bonaventure J. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. 1996 Apr;5(4):509–512. doi: 10.1093/hmg/5.4.509. [DOI] [PubMed] [Google Scholar]
  27. Shiang R., Thompson L. M., Zhu Y. Z., Church D. M., Fielder T. J., Bocian M., Winokur S. T., Wasmuth J. J. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994 Jul 29;78(2):335–342. doi: 10.1016/0092-8674(94)90302-6. [DOI] [PubMed] [Google Scholar]
  28. Shigematsu H., Takashima S., Otani K., Ieshima A. Neuropathological and Golgi study on a case of thanatophotoric dysplasia. Brain Dev. 1985;7(6):628–632. doi: 10.1016/s0387-7604(85)80013-9. [DOI] [PubMed] [Google Scholar]
  29. Su W. C., Kitagawa M., Xue N., Xie B., Garofalo S., Cho J., Deng C., Horton W. A., Fu X. Y. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature. 1997 Mar 20;386(6622):288–292. doi: 10.1038/386288a0. [DOI] [PubMed] [Google Scholar]
  30. Superti-Furga A., Eich G., Bucher H. U., Wisser J., Giedion A., Gitzelmann R., Steinmann B. A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia. Eur J Pediatr. 1995 Mar;154(3):215–219. doi: 10.1007/BF01954274. [DOI] [PubMed] [Google Scholar]
  31. Tavormina P. L., Rimoin D. L., Cohn D. H., Zhu Y. Z., Shiang R., Wasmuth J. J. Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Hum Mol Genet. 1995 Nov;4(11):2175–2177. doi: 10.1093/hmg/4.11.2175. [DOI] [PubMed] [Google Scholar]
  32. Tavormina P. L., Shiang R., Thompson L. M., Zhu Y. Z., Wilkin D. J., Lachman R. S., Wilcox W. R., Rimoin D. L., Cohn D. H., Wasmuth J. J. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. 1995 Mar;9(3):321–328. doi: 10.1038/ng0395-321. [DOI] [PubMed] [Google Scholar]
  33. Walker B. A., Murdoch J. L., McKusick V. A., Langer L. O., Beals R. K. Hypochondroplasia. Am J Dis Child. 1971 Aug;122(2):95–104. doi: 10.1001/archpedi.1971.02110020029001. [DOI] [PubMed] [Google Scholar]
  34. Webster M. K., D'Avis P. Y., Robertson S. C., Donoghue D. J. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol Cell Biol. 1996 Aug;16(8):4081–4087. doi: 10.1128/mcb.16.8.4081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Webster M. K., Donoghue D. J. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 1996 Feb 1;15(3):520–527. [PMC free article] [PubMed] [Google Scholar]
  36. Wongmongkolrit T., Bush M., Roessmann U. Neuropathological findings in thanatophoric dysplasia. Arch Pathol Lab Med. 1983 Mar;107(3):132–135. [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES