Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.
Activating mutations in the genes for fibroblast growth factor receptors 1-3 (FGFR1-3) are responsible for a diverse group of skeletal disorders. In general, mutations in FGFR1 and FGFR2 cause the majority of syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutations. Osteoglophonic dysplasia (OD) is a "crossover" disorder that has skeletal phenotypes associated with FGFR1, FGFR2, and FGFR3 mutations. Indeed, patients with OD present with craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as the rhizomelic dwarfism and nonossifying bone lesions that are characteristic of the disorder. We demonstrate here that OD is caused by missense mutations in highly conserved residues comprising the ligand-binding and transmembrane domains of FGFR1, thus defining novel roles for this receptor as a negative regulator of long-bone growth.
White
Kenneth E
KE
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Cabral
Jose M
JM
Davis
Siobhan I
SI
Fishburn
Tonya
T
Evans
Wayne E
WE
Ichikawa
Shoji
S
Fields
Joanna
J
Yu
Xijie
X
Shaw
Nick J
NJ
McLellan
Neil J
NJ
McKeown
Carole
C
Fitzpatrick
David
D
Yu
Kai
K
Ornitz
David M
DM
Econs
Michael J
MJ
D000328:Adult; D000595:Amino Acid Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics*; D004252:DNA Mutational Analysis; D005145:Face / Q000002:abnormalities*; D006801:Humans; D007621:Karyotyping; D008297:Male; D008445:Maxillofacial Development / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012886:Skull / Q000002:abnormalities*
D017468:Receptors, Fibroblast Growth Factor; C496348:FGFR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1