RGD Reference Report - Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. - Rat Genome Database

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Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.

Authors: Merrill, Amy E  Sarukhanov, Anna  Krejci, Pavel  Idoni, Brian  Camacho, Natalia  Estrada, Kristine D  Lyons, Karen M  Deixler, Hannah  Robinson, Haynes  Chitayat, David  Curry, Cynthia J  Lachman, Ralph S  Wilcox, William R  Krakow, Deborah 
Citation: Merrill AE, etal., Am J Hum Genet. 2012 Mar 9;90(3):550-7. doi: 10.1016/j.ajhg.2012.02.005. Epub 2012 Mar 1.
RGD ID: 12801468
Pubmed: PMID:22387015   (View Abstract at PubMed)
PMCID: PMC3309195   (View Article at PubMed Central)
DOI: DOI:10.1016/j.ajhg.2012.02.005   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Bent Bone Dysplasia Syndrome 1  IAGP 12801468DNA:missense mutations:cds:p.M391R and p.Y381D (human)RGD 
Bent Bone Dysplasia Syndrome 1  ISOFGFR2 (Homo sapiens)12801468; 12801468DNA:missense mutations:cds:p.M391R and p.Y381D (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Abnormal long bone morphology  IAGP 12801468DNA:missense mutations:cds:p.M391R and p.Y381DRGD 
Aplasia/Hypoplasia of the clavicles  IAGP 12801468DNA:missense mutations:cds:p.M391R and p.Y381DRGD 
Bowing of the long bones  IAGP 12801468DNA:missense mutations:cds:p.M391R and p.Y381DRGD 
Decreased calvarial ossification  IAGP 12801468DNA:missense mutations:cds:p.M391R and p.Y381DRGD 
Hypoplastic pubic bone  IAGP 12801468DNA:missense mutations:cds:p.M391R and p.Y381DRGD 
Objects Annotated

Genes (Rattus norvegicus)
Fgfr2  (fibroblast growth factor receptor 2)

Genes (Mus musculus)
Fgfr2  (fibroblast growth factor receptor 2)

Genes (Homo sapiens)
FGFR2  (fibroblast growth factor receptor 2)


Additional Information