Achondroplasia is an autosomal dominant trait, however, it has a very high spontaneous rate of mutation (about 90%). It is the result from a single point mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the patients, there is a Glycine to Arginine substitution at position 380 (also G380R and Gly380Arg) within the FGFR-3 transmembrane domain, resulting from a G to A point mutation at nucleotide 1138. FGFR-3 is a negative regulator of bone growth. Binding of fibroblast growth factors to the FGFR-3 receptor stimulates its tyrosine kinase activity in the cell, which leads to receptor over-activation. This FGF receptor is expressed by chondrocytes (Mature cartilage cells embedded in lacunae within the cartilage matrix) in the growth plate of developing long bones. Tyrosine kinase activates a signal transduction pathway that regulates enchondral ossification (formation of bone from cartilaginous tissue) by both inhibiting cell division and stimulating cell maturation and differentiation.
             Mutations in the FGFR-3 gene give rise to activation of the receptor in the absence of growth factors, thus causing abnormal long bone development. FGFR-3 mutations can be interpreted as gain-of-function mutations that activate the fundamentally negative growth control exerted by the FGFR-3 pathway. Position and type of mutation in the FGFR-3 gene determine the extent of over-activation and thus the severity of the skeletal abnormality.
             Homozygous achondroplasia, caused by the presence of two mutant alleles at nucleotide 1138 of the FGFR3 gene, is a severe disorder with radiological changes qualitatively different from those of achondroplasia. Early death results from respiratory insufficiency due to the small thoracic cage and neurological deficit from spinal stenosis.
             The 4.4kb cDNA contains an open reading frame of 2520 nucleotides, encoding a 840 residue protein. The open reading frame was followed by a 3' untranslated ...