Mutations that Cause Osteoglophonic Dysplasia Define Novel Roles for FGFR1 in Bone Elongation

• Published in: American journal of human genetics Vol. 76; no. 2; pp. 361 - 367
• Main Authors: White, Kenneth E., Cabral, Jose M., Davis, Siobhan I., Fishburn, Tonya, Evans, Wayne E., Ichikawa, Shoji, Fields, Joanna, Yu, Xijie, Shaw, Nick J., McLellan, Neil J., McKeown, Carole, FitzPatrick, David, Yu, Kai, Ornitz, David M., Econs, Michael J.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.02.2005; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Adult; Amino Acid Sequence; Biological and medical sciences; Bone Diseases, Developmental - genetics; Bones; DNA Mutational Analysis; Dwarfism; Face - abnormalities; General aspects. Genetic counseling; Genotype & phenotype; Humans; Karyotyping; Male; Maxillofacial Development - genetics; Medical genetics; Medical sciences; Middle Aged; Molecular Sequence Data; Mutation; Mutation, Missense; Pedigree; Receptor Protein-Tyrosine Kinases - genetics; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor - genetics; Skull - abnormalities; Human; Genetics; Dysplasia; Mutation; Bone; Elongation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/427956

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.