Molecular Medicine

, Volume 13, Issue 7–8, pp 422–442 | Cite as

Apert p.Ser252Trp Mutation in FGFR2 Alters Osteogenic Potential and Gene Expression of Cranial Periosteal Cells

  • Roberto D. Fanganiello
  • Andréa L. Sertié
  • Eduardo M. Reis
  • Erika Yeh
  • Nélio A. J. Oliveira
  • Daniela F. Bueno
  • Irina Kerkis
  • Nivaldo Alonso
  • Sérgio Cavalheiro
  • Hamilton Matsushita
  • Renato Freitas
  • Sergio Verjovski-Almeida
  • Maria Rita Passos-Bueno


Apert syndrome (AS), a severe form of craniosynostosis, is caused by dominant gain-of-function mutations in FGFR2. Because the periosteum contribution to AS cranial pathophysiology is unknown, we tested the osteogenic potential of AS periosteal cells (p.Ser252Trp mutation) and observed that these cells are more committed toward the osteoblast lineage. To delineate the gene expression profile involved in this abnormal behavior, we performed a global gene expression analysis of coronal suture periosteal cells from seven AS patients (p. Ser252Trp), and matched controls. We identified 263 genes with significantly altered expression in AS samples (118 upregulated, 145 downregulated; SNR ≥ |0.4|, P ≤ 0.05). Several upregulated genes are involved in positive regulation of cell proliferation and nucleotide metabolism, whereas several downregulated genes are involved in inhibition of cell proliferation, gene expression regulation, cell adhesion, and extracellular matrix organization, and in PIK3-MAPK cascades. AS expression profile was confirmed through real-time PCR of a selected set of genes using RNAs from AS and control cells as well as from control cells treated with high FGF2 concentration, and through the analysis of genes involved in FGF-FGFR signaling. Our results allowed us to: (a) suggest that AS periosteal cells present enhanced osteogenic potential, (b) unravel a specific gene expression signature characteristic of AS periosteal cells which may be associated with their osteogenic commitment, (c) identify a set of novel genes involved in the pathophysiology of AS or other craniosynostotic conditions, and (d) suggest for the first time that the periosteum might be involved in the pathophysiology of AS.



We are grateful to all of the patients and their relatives who participated in this work. We would like to thank Dr Hugo Armelin and Jaqueline Salotti for providing the FGFR2 antibodies and Y1 cell lineage; Regina Maki Sasahara for her help in earlier phases of the project; Dr Oswaldo Keith Okamoto for stimulating and useful discussions; Constância G Urbani for secretarial assistance; Eder Zuconni and Natassia Vieira for their contribution to the flow citometry experiments; Dr Alessandra S Gordonos and Fernanda Jehee for revision of the manuscript. This work is supported by grants from FundaÇão de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnolögico (CNPq).


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Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Roberto D. Fanganiello
    • 1
  • Andréa L. Sertié
    • 1
  • Eduardo M. Reis
    • 2
  • Erika Yeh
    • 1
  • Nélio A. J. Oliveira
    • 1
  • Daniela F. Bueno
    • 1
  • Irina Kerkis
    • 3
  • Nivaldo Alonso
    • 4
  • Sérgio Cavalheiro
    • 5
  • Hamilton Matsushita
    • 5
  • Renato Freitas
    • 6
  • Sergio Verjovski-Almeida
    • 2
  • Maria Rita Passos-Bueno
    • 1
  1. 1.Departamento. Genética e Biologia Evolutiva, Instituto de BiociênciasUSPSão PauloBrazil
  2. 2.Departamento de Bioquímica, Instituto de QuímicaUniversidade de São PauloSão PauloBrazil
  3. 3.Laboratório de GenéticaInstituto ButantãSão PauloBrazil
  4. 4.Departamento de Cirurgia Plástica, Faculdade de MedicinaUniversidade de São PauloSão PauloBrazil
  5. 5.Departamento de Neurologia, Escola Paulista de MedicinaUniversidade Federal de São PauloSão PauloBrazil
  6. 6.Centro de Atendimento ao FissuradoCuritibaBrazil

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