Several gain-of-function mutations in a
receptor tyrosine kinase,
fibroblast growth factor receptor 3 (FGFR3), cause
dwarfism in humans. Two particularly severe
dwarfisms, thanatophoric dysplasia type II (TDII) and
severe achondroplasia with developmental delay and acanthosis nigricans (
SADDAN), are associated with
glutamic acid (E) and
methionine (M) substitutions at the K650 residue in the
kinase domain. TDII is lethal at birth, whereas most of the
SADDAN patients survive the perinatal period. However, FGFR3 with the
SADDAN mutation is more activated than FGFR3 with the TDII mutation in vitro. To find out whether the K650M mutation also causes the
SADDAN phenotype, we introduced the corresponding point mutation (K644M) into the mouse Fgfr3 gene. Heterozygous mutant mice show a phenotype similar to human
SADDAN, e.g. the majority of the
SADDAN mice survive the perinatal period. This suggests that the survival of
SADDAN patients is indeed attributed to the K650M mutation in FGFR3. The long bone abnormalities in
SADDAN mice are milder than the TDII model. In addition, overgrowth of the cartilaginous tissues is observed in the rib cartilage, trachea and nasal septum. The FGF
ligand at the low concentration differentially activates Map
kinase in primary chondrocyte cultures from wild-type and
SADDAN mice. Comparisons of the molecular bases of the phenotypic differences in
SADDAN and TDII mice may increase our understanding of the factors that influence the severity in these two related skeletal dysplasias.