Achondroplasia has recently been shown to result from a Gly to Arg substitution in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3). By substituting the transmembrane domain of the Neu receptor tyrosine kinase with the transmembrane domains of wild-type and mutant FGFR3, the Arg380 mutation in FGFR3 is shown to activate both the kinase and transforming activities of this chimeric receptor. Residues with side chains capable of participating in hydrogen bond formation, including Glu, Asp, and to a lesser extent, Gln, Hisand Lys, are able to substitute for the activating Arg380 mutation. The Arg380 point mutation also causes ligand-independent stimulation of the tyrosine kinase activity of FGFR3 itself, and greatly increased constitutive levels of phosphotyrosine on the receptor. As a result, it limits the formation of bone from cartilage (a process called calcification), particularly in long bones. FGFR3 also plays an important role in cell growth and division, determination of cell type, formation of blood vessels, wound healing and embryo development.
In heterozygous state, achondroplasia is non-lethal with normal life span and normal intelligence. However, they are at risk like cervicomedullary compression (compression of the upper spinal cordat the base of the brain), spinal stenosis, obesity, obstructive sleep problem. In homozygous state, achondroplasia is a lethal condition in the early few months of life because of severe rib cage deformity that results in respiratory insufficiency.
