ACTIVATION OF STAT1 BY MUTANT FIBROBLAST GROWTH-FACTOR RECEPTOR IN THANATOPHORIC DYSPLASIA TYPE-II DWARFISM

The achondroplasia class of chondrodysplasias comprises the most commo n genetic forms of dwarfism in humans and includes achondroplasia, hyp ochondroplasia and thanatophoric dysplasia types I and II (TDI and TDI I), which are caused by different mutations in a fibroblast growth-fac tor receptor FGFR3 (ref, 1), The molecular mechanism and the mediators of these FGFR3-related growth abnormalities are not known, Here we sh ow that mutant TDII FGFR3 has a constitutive tyrosine kinase activity which can specifically activate the transcription factor Stat1 (for si gnal transducer and activator of transcription)(2,3). Furthermore, exp ression of TDII FGFR3 induced nuclear translocation of Stat1, expressi on of the cell-cycle inhibitor p21(WAF1/CIP1), and growth arrest of th e cell. Thus, TDII FGFR3 may use Stat1 as a mediator of growth retarda tion in bone development, Consistent with this, Stat1 activation and i ncreased p21(WAF1/CIP1) expression was found in the cartilage cells fr om the TDII fetus, but not in those from the normal fetus, Thus, abnor mal STAT activation and p21(WAF1/CIP1) expression by the TDII mutant r eceptor may be responsible for this FGFR3-related bone disease.