title: Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I.
abstract: Thanatophoric dysplasia type I (TDI) is a neonatal lethal skeletal dysplasia caused by several mutations in the extracellular domain of fibroblast growth factor receptor 3. These mutations occur either in the Ig2-Ig3 linker domain or in the extracellular juxtamembrane domain, and all involve mutation of the wild-type residue to Cys. In all cases, the presence of the mutant Cys residue allows the receptor to dimerize abnormally, resulting in ligand-independent activation. This is also manifested by increased biological signaling, increased tyrosine phosphorylation, and in vitro kinase activity associated with dimeric receptors. These results suggest that TDI is caused by Cys-mediated intermolecular disulfide bonding, leading to constitutive receptor activation as a result of these mutations. Mutations causing TDI are discussed with respect to activating mutations in other receptors that are implicated in human disease.
authors.affiliation: Department of Chemistry and Biochemistry, Center for Molecular Genetics, University of California at San Diego, La Jolla 92093-0367, USA.
authors.forename: P Y
authors.initials: PY
authors.lastname: d'Avis
authors.forename: S C
authors.initials: SC
authors.lastname: Robertson
authors.forename: A N
authors.initials: AN
authors.lastname: Meyer
authors.forename: W M
authors.initials: WM
authors.lastname: Bardwell
authors.forename: M K
authors.initials: MK
authors.lastname: Webster
authors.forename: D J
authors.initials: DJ
authors.lastname: Donoghue
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D019281:Dimerization; D006801:Humans; D051379:Mice; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013796:Thanatophoric Dysplasia / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse