title: Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis.
abstract: Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several human skeletal dysplasias, including the most common form of dwarfism, achondroplasia. Here we show that a glycine-to-cysteine substitution at position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human achondroplasia. Accordingly, homozygous mice were more severely affected than heterozygotes. The resulting mutant mice exhibited macrocephaly and shortened limbs due to retarded endochondral bone growth and premature closure of cranial base synchondroses. Compared with their wild-type littermates, mutant mice growth plates shared an expanded resting zone and narrowed proliferating and hypertrophic zones, which is correlated with the activation of Stat proteins and upregulation of cell-cycle inhibitors. Reduced bone density is accompanied by increased activity of osteoclasts and upregulation of genes that are related to osteoblast differentiation, including osteopontin, osteonectin, and osteocalcin. These data reveal an essential role for FGF/FGFR3 signals in both chondrogenesis and osteogenesis during endochondral ossification.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Adar
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: E O
authors.initials: EO
authors.lastname: Monsonego
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: P V
authors.initials: PV
authors.lastname: Hauschka
authors.forename: A
authors.initials: A
authors.lastname: Yayon
authors.forename: C X
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000130:Achondroplasia / Q000235:genetics*; D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D002460:Cell Line; D020219:Chondrogenesis / Q000235:genetics*; D019281:Dimerization; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D018390:Gene Targeting; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009154:Mutation; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D015676:Osteonectin / Q000378:metabolism; D053495:Osteopontin; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011859:Radiography; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012795:Sialoglycoproteins / Q000378:metabolism; D014162:Transfection
chemical_list: D015676:Osteonectin; D017468:Receptors, Fibroblast Growth Factor; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D015675:Osteocalcin; D053495:Osteopontin; D005346:Fibroblast Growth Factors; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3