Thus it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain.
Within the past year, the achondroplasia locus has been mapped to 4p 16.3 (refs 5-7) and mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in patients with the disorder.
This observation indicates allelic heterogeneity and confirms the role of mutations in the transmembrane domain of FGFR-3 in the pathogenesis of achondroplasia.
Given the homogeneity of mutations within the fibroblast growth factor receptor 3 (FGFR3) gene in the vast majority of patients with Ach, FGFR3 mutational analysis can be offered in every instance where a short-limb disorder is ultrasonographically detected in the latter stages of pregnancy.
These results suggest that the molecular basis of achondroplasia is unregulated signal transduction through FGFR3, which may result in inappropriate cartilage growth plate differentiation and thus abnormal long bone development.
These results together with our earlier observation that achondroplasia results from constitutive activation of the related receptor FGFR3, leads to the prediction that other malformation syndromes attributed to FGFRs, such as Pfeiffer syndrome and Thanatophoric dysplasia, also arise from constitutive receptor activation.
We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.
The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity: 100% of patients examined exhibited mutations in the transmembrane domain of FGFR-3.
Thus, it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.