European Journal of Pediatrics

, Volume 154, Issue 3, pp 215–219 | Cite as

A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia

  • A. Superti-Furga
  • B. Steinmann
  • R. Gitzelmann
  • G. Eich
  • A. Giedion
  • H. U. Bucher
  • J. Wisser
  • A. Superti-Furga
Medical Genetics Original Paper

Abstract

Achondroplasia, the most common form of chondrodysplasia, has been associated with mutations in the gene of the fibroblast growth factor receptor-3 (FGFR-3) on chromosome 4p. All 39 achondroplasia alleles studied so far carried point mutations which caused the same amino acid exchange, a substitution of glycine by arginine at position 380 (G380R) in the transmembrane domain of the receptor. We report on a newborn with achondroplasia who does not carry a G380R mutation but has a mutation causing substitution of a nearby glycine with a cysteine (G375C). This observation indicates allelic heterogeneity and confirms the role of mutations in the transmembrane domain of FGFR-3 in the pathogenesis of achondroplasia.

Key words

Chondrodysplasia Dominant mutation Amino acid substitution Allelic heterogeneity 

Abbreviations

FGFR-3

fibroblast growth factor receptor-3

G-to-A

guanosine-to-adenosine transition

G-to-C

guanosine-to-cytidine transversion

G-to-T

guanosine-to-thymidine transversion

G375C

glycine-to-cysteine substitution at position 375

G380R

glycine-to-arginine substitution at position 380

PCR

polymerase chain reaction

SSCP

single-strand conformation polymorphism

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Horton WA, Hecht JT (1993) The chondrodysplasias. In: Royce PM, Steinmann B (eds) Connective tissue and its heritable disorders—molecular, genetics, and medical aspects. Wiley-Liss, New York, pp 641–675Google Scholar
  2. 2.
    Keegan K, Johnson DE, Williams LT, Hayman MJ, (1991) Isolation of an additional member of the fibroblast growth receptor family, FGFR-3. Proc Natl Acad Sci USA 88:1095–1099PubMedGoogle Scholar
  3. 3.
    Langer LO, Baumann PA, Gorlin RJ (1967) Achondroplasia. Am J Roentgenol 100:12–26Google Scholar
  4. 4.
    Le Merrer M, Rousseau F, Legeal-Mallet L, Landais JC, Pelet A, Bonaventure J, Sanak M, Weissenbach J, Stoll C, Munnich A, Maroteaux P (1994) A gene for achondroplasia-hypochondroplasia maps to chromosome 4p. Nature Genet 6:318–321CrossRefPubMedGoogle Scholar
  5. 5.
    Ornitz DM, Leder P (1992) Ligand specificity and heparin dependence of fibroblast growth factor receptors 1 and 3. J Biol Chem 267:16305–16311PubMedGoogle Scholar
  6. 6.
    Pasquale EB (1990) A distinctive family of embryonic protein-tyrosine kinase receptors. Proc. Natl Acad Sci USA 87:5812–5816PubMedGoogle Scholar
  7. 7.
    Rimoin DL, Lachman RS (1993) Genetic disorders of the osseous skeleton. In: Beighton P (ed) Heritable disorders of connective tissue, 5th ed. Mosby-Year Book, St. Louis, pp 557–689Google Scholar
  8. 8.
    Robinow M, Chumlea WC (1982) Standards for limb bone length ratios in children. Radiology 143:433–436PubMedGoogle Scholar
  9. 9.
    Rousseau F, Bonaventure J, Legeal-Mallet L, Pelet A, Rozet JM, Maroteaux P, Lemerrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254CrossRefPubMedGoogle Scholar
  10. 10.
    Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR-3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–342CrossRefPubMedGoogle Scholar
  11. 11.
    Superti-Furga A, Steinmann B, Duc G, Gitzelmann R (1991) Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation. Eur J Pediatr 150:493–497PubMedGoogle Scholar
  12. 12.
    Thompson LM, Plummer S, Schalling M, Altherr MR, Gusella JF, Housman DE, Wasmuth JJ (1991) A gene encoding a fibroblast growth factor receptor isolated from the Huntington disease gene region of human chromosome 4. Genomics 11:1133–1142CrossRefPubMedGoogle Scholar
  13. 13.
    Velinov M, Slaugenhaupt SA, Stoilov I, Scott CI, Gusella JF, Tsipouras P (1994) The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genet 6:314–317CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • A. Superti-Furga
    • 1
  • B. Steinmann
    • 1
  • R. Gitzelmann
    • 1
  • G. Eich
    • 2
  • A. Giedion
    • 2
  • H. U. Bucher
    • 3
  • J. Wisser
    • 4
  • A. Superti-Furga
    • 5
  1. 1.Division of Metabolism, Department of PediatricsUniversity of ZurichSwitzerland
  2. 2.Division of Radiology, Department of PediatricsUniversity of ZurichSwitzerland
  3. 3.Division of Neonatology, Department of PediatricsUniversity of ZurichSwitzerland
  4. 4.Department of ObstetricsUniversity of ZurichSwitzerland
  5. 5.University Children's HospitalZurichSwitzerland

Personalised recommendations