Nature Genetics
13, 233 - 237 (1996)
doi:10.1038/ng0696-233
Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasiaMichael C. Naski1, Qing Wang1, Jingsong Xu1
& David M. Ornitz1
1Department of Molecular Biology and Pharmacology, Washington University School of MedicineSt. Louis, Missouri 63110, USA Correspondence should be addressed to D.M.O. The longitudinal growth of the skeleton arises from the continuous process of endochondral ossification occurring at the ends of growing long bones. Dwarfism results when this process is disrupted, as in the autosomal dominant human skeletal diseases hypochondroplasia (HCH)1, achondroplasia (ACH)2 and thanatophoric dys-plasia (TD)3. Interestingly, these disorders display a graded spectrum of phenotypic severity and are the result of distinct missense mutations in the fibroblast growth factor receptor 3 gene (FGFR3). TD, characterized by neonatal lethality and profound dwarfism, is the result of FGFR3 mutations, including an R248C substitution in the extracellular domain or a K650E substitution in the tyrosine kinase (TK) domain4. ACH, which is non-lethal and presents less severe dwarfism, results almost exclusively from a G380R substitution in the transmembrane domain5, 6. Homozy-gous achondroplasia resembles the phenotype of TD7. In this report the effect of the ACH and TD mutations on the activity and regulation of FGFR3 are analysed. We showed that each of the mutations constitutively activate the receptor, as evidenced by ligand-independent receptor tyro-sine phosphorylation and cell proliferation. Moreover, the mutations that are responsible for TD were more strongly activating than the mutation causing ACH, providing a biochemical explanation for the observation that the phenotype of TD is more severe than that of ACH
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