Achondroplasia and related chondrodysplasias are caused by heterozygous mutations of fibroblast growth factor receptor 3 (FGFR3). Virtually all patients with achondroplasia have the same mutation, and all of the FGFR3 mutations activate the FGFR3 signal transduction pathways. There is remarkable correlation between specific mu t a t i o n s a n d t h e s e v e r i t y o f c l i n i c a l p h e n o t y p e s manifestations. The mutations activate the FGFR3 transmembrane receptor by promoting or stabilizing receptor dimerization or by activating kinase activity, in the absence of FGF ligand binding. FGFR3 signals are transmitted through several pathways; the best defined involves activation of STAT1 and induction of the antimitotic protein, p21, in the growth plate. Attempts are underway to experimentally model achondroplasia in transgenic mice by expressing mutant FGFR3 receptors in cartilage
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