Mutations in the Fibroblast Growth Factor Receptor 3 Gene Result in a Variety of Skeletal Dysplasias

The phenotypic variation of skeletal dysplasias points to a complex etiology for this class of disorders. Some of the more common skeletal dysplasias, however, have been shown to be a consequence of a limited number of mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.

These skeletal dysplasias include:
  • achondroplasia (ACH), the most common genetic form of dwarfism
  • thanatophoric dysplasia (TD1 and TD2), the most common form of sporadic, lethal skeletal dysplasia
  • hypochondroplasia (HCH), a more mild skeletal dysplasia which resembles achondroplasia
  • non-syndromic coronal craniosynostosis

    The figure below shows a schematic representation of the FGFR3 gene and the relative positions of a variety of mutations known to result in skeletal dysplasias. The gene structure includes a putative leader sequence (L), a series of three immunoglobulin-like domains (Ig1, Ig2, Ig3), a transmembrane domain (TM), and segments of a tyrosine kinase domain (TK1 and TK2).

    A summary of the mutations presently known in the FGFR3 gene and their approximate relative percentages in various skeletal dysplasias is shown in the table below.


    % of mutations
    TD 1
    nt742 C>T
    TD 1
    nt746 C>G
    Nonsyndromic craniosynostosis
    nt749 C>G
    TD 1
    nt1108 G>T
    TD 1
    nt1111 A>T
    TD 1
    nt1118 A>G
    nt1138 G>A or G>C
    nt1620 C>A or C>G
    40 - 50
    TD 2
    nt1948 A>G
    > 99
    TD 1
    nt1949 A>T
    TD 1
    X807G or X807R or X807C
    nt2419 T>G or nt2419 T>A or nt2421A>T


    Achondroplasia is the most common form of autosomal dominant inherited dwarfism. Its incidence has been estimated to range from 1/15,000 to 1/77,000. The vast majority of cases (80-90%) are due to new mutations that have been reported to be associated with an increase in paternal age. The gene was mapped to 4p16.3 and eventually shown to result from distinct mutations in the fibroblast growth factor receptor gene, FGFR3. A review of 193 reported cases in 1995 (Bellus et al., (1995) Am. J. Hum. Genet. 56:368-373) showed that virtually all were the result of a specific glycine to arginine substitution at amino acid 380 of FGFR3. This non-conservative amino acid substitution in the transmembrane domain was due either to nucleotide 1138 G > A (96.9%) or 1138 G>C (2.6%). These substitutions are readily detected by the gain of a Sfc I or Msp I site, respectively.

    As shown in the figure below, the affected patient shows the gain of the most common FGFR3 mutation, the 1138 G>A. Lane M shows DNA size markers, lane B shows a negative DNA control, lane U shows the uncut FGFR3 PCR product, while the pairs of lanes show on the right a negative control and the proband, respectively, digested either with Sfc I or Msp I. The red arrows indicate restriction fragments obtained by the gain of an Sfc I site in the proband.

    Thanatophoric Dysplasia

    The most common sporadic, neonatal lethal skeletal dysplasia, thanatophoric dysplasia, has been found to be due to a limited number of mutations in the FGFR3 gene (Tavormina et al (1995) Nature Genetics 9:321-328; Wilcox et al. (1998) Am. J. Hum. Genet. 78:274-281). The most common of these, R248C, accounts about one-half of the cases. A variety of clinical features have been found that can distinguish TD1 from TD2 (Wilcox et al., 1998). These features include the presence or absence of cloverleaf skull and the presence of straight or curved femora. The nt742 C>T point mutation resulting in the R248C substitution can be detected by the gain of a Bsi HKA I site. An example of this analysis is shown below. As this severe, lethal skeletal dysplasia is often observed prenatally, it may be desirable for a rapid confirmation of the clinical diagnosis for appropriate clinical management. CompGene typically can provide prenatal results on direct amniotic fluid within 24 - 48 hours after receipt. Neonate samples of cord blood can be similarly evaluated.