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Case Reports
. 2005 Feb;76(2):361-7.
doi: 10.1086/427956. Epub 2004 Dec 28.

Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation

Kenneth E White  1 , Jose M Cabral, Siobhan I Davis, Tonya Fishburn, Wayne E Evans, Shoji Ichikawa, Joanna Fields, Xijie Yu, Nick J Shaw, Neil J McLellan, Carole McKeown, David Fitzpatrick, Kai Yu, David M Ornitz, Michael J Econs
Affiliations
Case Reports

Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation

Kenneth E White et al. Am J Hum Genet. 2005 Feb.

Abstract

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.

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Figures

Figure 1
Figure 1
Kindred including patients 1 and 2 with OD. a, The proband (patient 1, shown here after multiple corrective surgeries). He had severe craniofacial abnormalities, including craniosynostosis, telechanthus, and facial hypoplasia, as did his father (patient 2) and brother (infant and adult photographs of the brother are shown). b, Patient 2; note reduced stature. c, The heterozygous 1115G→A (Y372C) missense mutation in patients 1 and 2, as detected by DNA sequencing. This change was not found in normal controls or in the proband’s grandmother.
Figure 2
Figure 2
Patient 3. a, Midface hypoplasia with low-set ears and telechanthus. b, Radiograph of the lower leg, revealing severe lesions at the metaphases, as well as shortened bone length and decreased mineral density. c, The 929T→A (N330I) missense mutation of patient 3.
Figure 3
Figure 3
Patient 4. a, Craniosynostosis, midface hypoplasia, and telechanthus. b, Radiograph of the femur, showing lesions at metaphysis (arrow). c, The 1135T→C (C379R) mutation of patient 4.
Figure 4
Figure 4
Characteristics of OD mutations. a, Activation of FGFR1 and Y372C FGFR1 tested using cotransfection of wild-type FGFR1 and Y372C mutant FGFR1 with an FGFR1-responsive osteocalcin promoter-luciferase construct. Y372C FGFR1 had a 9-fold greater basal activity, compared with that of wild-type FGFR1 (P<.01), and showed increased activity with FGF2 as ligand (20 pM, P<.01; 200 pM, P<.02; 2,000 pM, P<.03). b, Structure of FGFR1, with the relevant domains labeled. D1–3 = extracellular immunoglobulin-like domains that comprise the FGF-binding domain; TM = transmembrane region; TK = tyrosine kinase domains 1–2. The thick bold line within D3 represents the known IIIb(exon 8)/IIIc(exon 9) splicing region. The positions of the OD mutations within FGFR1 exons 9 and 10 are indicated. In the partial protein-sequence alignment of FGFR1-4 (bottom), the location of conserved residues with OD FGFR1 mutations are boxed, and the transmembrane domains encoded by sequences within exon 10 are underlined.
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References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for OD) - PubMed

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