Two lines of evidence speak against mutation in COL2A1 as the cause of achondroplasia: (1) no gross rearrangements are seen on Southern blot analysis of DNA from probands, and (2) linkage studies in multiplex families demonstrate discordant inheritance of achondroplasia and COL2A1 alleles.
These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or pseudoachondroplasia in these families.
The sequence changes were used to demonstrate discordant segregation between the COL10A1 locus and achondroplasia and pseudoachondroplasia, in nuclear families.
Pilot studies of short-term growth hormone therapy in patients with achondroplasia and hypochondroplasia and nasal-osteocalcin therapy in osteogenesis imperfecta patients has been described, but the long-term effectiveness of these treatments remains to be determined.
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.