title: Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.
abstract: Fibroblast growth factor receptor 2 (FGFR2) is a crucial regulator of bone formation during embryonic development. Both gain and loss-of-function studies in mice have shown that FGFR2 maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells. We have identified de novo FGFR2 mutations in a sporadically occurring perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Histological analysis of the long bones revealed that the growth plate contained smaller hypertrophic chondrocytes and a thickened hypercellular periosteum. Four unrelated affected individuals were found to be heterozygous for missense mutations that introduce a polar amino acid into the hydrophobic transmembrane domain of FGFR2. Using diseased chondrocytes and a cell-based assay, we determined that these mutations selectively reduced plasma-membrane levels of FGFR2 and markedly diminished the receptor's responsiveness to extracellular FGF. All together, these clinical and molecular findings are separate from previously characterized FGFR2 disorders and represent a distinct skeletal dysplasia.
authors.affiliation: Department of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, 90048, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Merrill
authors.forename: Anna
authors.initials: A
authors.lastname: Sarukhanov
authors.forename: Pavel
authors.initials: P
authors.lastname: Krejci
authors.forename: Brian
authors.initials: B
authors.lastname: Idoni
authors.forename: Natalia
authors.initials: N
authors.lastname: Camacho
authors.forename: Kristine D
authors.initials: KD
authors.lastname: Estrada
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lyons
authors.forename: Hannah
authors.initials: H
authors.lastname: Deixler
authors.forename: Haynes
authors.initials: H
authors.lastname: Robinson
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: D000595:Amino Acid Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism; D005333:Fetus / Q000002:abnormalities / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012863:Skeleton
chemical_list: D005346:Fibroblast Growth Factors; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2