Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling Amy E. Merrill, Anna Sarukhanov, Pavel Krejci, Brian.

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Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient Canonical FGF Signaling Amy E. Merrill, Anna Sarukhanov, Pavel Krejci, Brian Idoni, Natalia Camacho, Kristine D. Estrada, Karen M. Lyons, Hannah Deixler, Haynes Robinson, David Chitayat, Cynthia J. Curry, Ralph S. Lachman, William R. Wilcox, Deborah Krakow The American Journal of Human Genetics Volume 90, Issue 3, Pages 550-557 (March 2012) DOI: 10.1016/j.ajhg.2012.02.005 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical and Radiographic Findings in BBD-FGFR2 Type (A–E) Craniofacial abnormalities include hypertelorism, microganthia, microstomia, low-set posteriorly rotated ears, prenatal teeth, and a flattened midface. (F–N) Radiographic analysis revealed reduced mineralization of the calvarial vault (F and G), coronal craniosynostosis (arrow in G), hypoplastic clavicles (arrows in H and I), bent long bones in the lower extremities and hypoplastic pubis (J–L, arrow in K), and boney nodules on the phalanges and metacarpals (M and N). The American Journal of Human Genetics 2012 90, 550-557DOI: (10.1016/j.ajhg.2012.02.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Histologic Analysis of the Distal Femoral Growth Plate in BBD-FGFR2 Type Longitudinal sections through the femoral growth plate of a normal control matched for growth stage (A) and two BBD-FGFR2-type individuals, R07-401 (B) and R08-041 (C), showed that cellular organization was largely normal with subjectively smaller hypertrophic chondrocytes. (D–F) The long-bone periosteum (p) in BBD-FGFR2-type individuals R07-401 and R08-041 was hypercellular and enlarged compared to that of the control. The American Journal of Human Genetics 2012 90, 550-557DOI: (10.1016/j.ajhg.2012.02.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 FGFR2 Mutational Analysis in BBD-FGFR2-Type Families Sequencing chomatograms demonstrated de novo heterozygous mutations in exon 9 of FGFR2 in affected individuals from the four unrelated families studied. Affected individuals R07-401 (A), R08-041 (B), and R96-252 (C) shared the same de novo heterozygous mutation, c.1172T>G (p.Met391Arg). (D) R05-427 was heterozygous for c.1141T>G (p.Tyr381Asp). (E) All mutations (bolded) were localized to a highly conserved region within the transmembrane domain. (F–H) TMHMM plots predicted the probability (y axis) that the amino acid sequences (x axis) of FGFR2, FGFR2Met391Arg, and FGFR2Tyr381Asp are located outside the cell (pink bar), inside the cell (blue bar), or within the membrane (red bar). The American Journal of Human Genetics 2012 90, 550-557DOI: (10.1016/j.ajhg.2012.02.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutant FGFR2Met391Arg Showed Deficient Plasma-Membrane Localization and Reduced Responsiveness to Extracellular FGF (A) Quantitative PCR of tibial growth-plate cDNA in the control and R07-401 showed that R07-401 had slightly elevated levels of FGFR2 expression. (B) Immunoblot analysis—with FGFR2 antibodies that recognize either the intracellular domain (anti-FGFR2) or extracellular domain (anti-FGFR2ex) of total lysates from primary chondrocytes showed that there were fewer highly glycosylated forms of FGFR2 in R07-401 chondrocytes than in the control (∗bands). Biotin labeling and purification of cell-surface proteins identified less surface FGFR2 in R07-401 cells than in the control. (C) Immunofluorescent detection with an antibody recognizing the intracellular domain of FGFR2 (red) and the membrane marker WGA (green) in primary chondrocytes localized FGFR2 to the membrane and nuclei of control chondrocytes. (D) Although membrane localization was undetectable in R07-401 cells, nuclear receptor levels were retained. (E) The FGFR2ex antibody detected receptor in the plasma membrane and nuclei of control cells. (F) In R07-401 cells, the FGFR2ex antibody detected receptor in the nuclei and juxtanuclear intracellular inclusions (arrow). (G and H) BaF3 cells overexpressing either wild-type or mutant FGFR2 were immuolabeled for FGFR2 (red) and WGA (green) and showed that FGFR2WT localized to the membrane whereas FGFR2Met391Arg was restricted to the nucleus (blue). (I) Immunoblot analysis of lysates from BaF3 cells overexpressing FGFR2WT or FGFR2Met391Arg showed that FGFR2Met391Arg-expressing cells were unable to induce phosphorylation of ERK1/2 upon 30 min of stimulation with either FGF2 or FGF18. The American Journal of Human Genetics 2012 90, 550-557DOI: (10.1016/j.ajhg.2012.02.005) Copyright © 2012 The American Society of Human Genetics Terms and Conditions