A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia.

Hypochondroplasia (MIM 146000) is an autosomal dominant skeletal dysplasia with skeletal features similar to but milder than those seen in achondroplasia. Within the past year, the achondroplasia locus has been mapped to 4p 16.3 (refs 5-7) and mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in patients with the disorder. More than 95% of 242 cases reported so far are accounted for by a single Gly380Arg mutation. McKusick et al. proposed that achondroplasia and hypochondroplasia are allelic based on the similarities in phenotype between the two disorders and the identification of a severely dwarfed individual whose father had achondroplasia and whose mother had hypochondroplasia. There is also genetic linkage evidence that hypochondroplasia and achondroplasia map to the same locus. We therefore began a systematic screening of FGFR3 to detect mutations in patients with hypochondroplasia. We now report a single FGFR3 mutation found in 8 out of 14 unrelated patients with hypochondroplasia. This mutation causes a C to A transversion at nucleotide 1620, resulting in an Asn540Lys substitution in the proximal tyrosine kinase domain.