CONSTITUTIVE ACTIVATION OF FIBROBLAST GROWTH-FACTOR RECEPTOR-3 BY THETRANSMEMBRANE DOMAIN POINT MUTATION FOUND IN ACHONDROPLASIA

Achondroplasia, the most common genetic form of dwarfism, is an autoso mal dominant disorder whose underlying mechanism is a defect in the ma turation of the cartilage growth plate of long bones, Achondroplasia h as recently been shown to result from a Gly to Arg substitution in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR 3), although the molecular consequences of this mutation have not been investigated, By substituting the transmembrane domain of the Neu rec eptor tyrosine kinase with the transmembrane domains of wild-type and mutant FGFR3, the Arg380 mutation in FGFR3 is shown to activate both t he kinase and transforming activities of this chimeric receptor, Resid ues with side chains capable of participating in hydrogen bond formati on, including Glu, Asp, and to a lesser extent, Gin, His and Lys, were able to substitute for the activating Arg380 mutation, The Arg380 poi nt mutation also causes ligand-independent stimulation of the tyrosine kinase activity of FGFR3 itself, and greatly increased constitutive l evels of phosphotyrosine on the receptor, These results suggest that t he molecular basis of achondroplasia is unregulated signal transductio n through FGFR3, which may result in inappropriate cartilage growth pl ate differentiation and thus abnormal long bone development, Achondrop lasia may be one of a number of congenital disorders where constitutiv e activation of a member of the FGFR family leads to developmental abn ormalities.