The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation

A point mutation, Gly380Arg, in the transmembrane domain of fibroblast grow th factor receptor 3 (FGFR3) leads to achondroplasia, the most common form of genetic dwarfism in humans. This substitution was suggested to enhance m utant receptor dimerization, leading to constitutive, ligand-independent ac tivation. We found that dimerization and activation of the G380R mutant rec eptor are predominantly ligand dependent. However, using both transient and stable transfections, we found significant overexpression only of the muta nt receptor protein. Metabolic pulse-chase experiments, cell surface labeli ng, and kinetics of uptake of radiolabeled ligand demonstrated a selective delay in the down-regulation of the mutant receptor. Moreover, this recepto r was now resistant to ligand-mediated internalization, even at saturating ligand concentrations. Finally, transgenic mice expressing the human G380R mutant receptor under the mouse receptor transcriptional control demonstrat ed a markedly expanded area of FGFR3 immunoreactivity within their epiphyse al growth plates, compatible with an in vivo defect in receptor down-regula tion. We propose that the achondroplasia mutation G380R uncouples ligand-me diated receptor activation from down-regulation at a site where the levels and kinetics of FGFR3 signals are crucial for chondrocyte maturation and bo ne formation.