title: The missense mutation W290R in Fgfr2 causes developmental defects from aberrant IIIb and IIIc signaling.
abstract: Missense mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) have been identified in human craniosynostotic syndromes such as Crouzon (CS) and Pfeiffer (PS). FGFR2 has two major isoforms, IIIb and IIIc, generated through alternative splicing with their own temporal, spatial, and ligand-binding specificities. In this study, we report the identification and characterization of a missense mutation in codon 290 of murine Fgfr2 (W290R). The defects in W290R mutants are suggestive of disruption of signalling in both IIIb and IIIc isoforms of the Fgfr2 gene. Heterozygous mutants presented with features resembling those found in patients with CS. Fgfr2(W290R) homozygotes displayed constitutive FGFR2 activation with increased, but correct tissue-specific, expression of the IIIb and IIIc isoforms in many of the defective organs. Our Fgfr2(W290R) mouse model thus represents an excellent mouse model of CS to probe the many questions around the pathogenesis of craniosynostotic birth defects consequent to defects in FGF signaling.
authors.affiliation: Faculty of Dentistry, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Mai
authors.forename: K
authors.initials: K
authors.lastname: Wei
authors.forename: A
authors.initials: A
authors.lastname: Flenniken
authors.forename: S L
authors.initials: SL
authors.lastname: Adamson
authors.forename: J
authors.initials: J
authors.lastname: Rossant
authors.forename: J E
authors.initials: JE
authors.lastname: Aubin
authors.forename: S-G
authors.initials: SG
authors.lastname: Gong
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D003394:Craniofacial Dysostosis / Q000235:genetics; D003398:Craniosynostoses / Q000235:genetics; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D051497:Receptor, Fibroblast Growth Factor, Type 2