A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia

Fibroblast growth factor receptor 3 (FGFR3) is a glycoprotein that belongs to the family of tyrosine kinase receptors. Specific mutations in the FGFR3 gene are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. Hypochon droplasia (HCH), the mildest form of this group of short-limbed dwarfism di sorders, results in similar to 60% of cases from a mutation in the intracel lular FGFR3-tyrosine kinase domain. The remaining cases may either be cause d by defects in other FGFR gene regions or other yet unidentified genes. We describe a novel HCH mutation, the first found outside the common mutation hot spot of this condition. This point mutation, an N328I exchange in the extracellular Ig domain III of the receptor, seems to be unique as it affec ts a putative N-glycosylation site that is conserved between different FGFR s and species. The amino acid exchange itself most probably has no impact o n the three-dimensional structure of the receptor domain, suggesting that t he phenotype is the result of altered receptor glycosylation and its pathop hysiological consequences.