Kenneth E. White, Jose M. Cabral, Siobhan I

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Mutations that Cause Osteoglophonic Dysplasia Define Novel Roles for FGFR1 in Bone Elongation Kenneth E. White, 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 The American Journal of Human Genetics Volume 76, Issue 2, Pages 361-367 (February 2005) DOI: 10.1086/427956 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2005 76, 361-367DOI: (10.1086/427956) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2005 76, 361-367DOI: (10.1086/427956) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2005 76, 361-367DOI: (10.1086/427956) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2005 76, 361-367DOI: (10.1086/427956) Copyright © 2005 The American Society of Human Genetics Terms and Conditions