Mild isolated craniosynostosis due to a novel FGFR3 mutation, p.Ala334Thr

Authors

  • Eva Barroso,

    1. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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  • Virginia Pérez-Carrizosa,

    1. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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  • Ignacio García-Recuero,

    1. Unit of Oral and Maxilofacial Surgery, Hospital Universitario Doce de Octubre, Madrid, Spain
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  • Marc J. Glucksman,

    1. Department of Biochemistry and Molecular Biology, Midwest Proteome Center, Rosalind Franklin University of Medicine and Science, Chicago Medical School, Chicago, Illinois
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  • Andrew O. Wilkie,

    1. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
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  • Sixto García-Minaur,

    1. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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  • Karen E. Heath

    Corresponding author
    1. Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
    • Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, P° Castellana 261, 28046 Madrid, Spain.
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  • How to Cite this Article: Barroso E, Pérez-Carrizosa V, García-Recuero I, Glucksman MJ, Wilkie AO, García-Minaur S, Heath KE. 2011. Mild isolated Craniosynostosis due to a novel FGFR3 mutation, p.Ala334Thr. Am J Med Genet Part A 155: 3050–3053.

Abstract

Craniosynostosis is the premature fusion of one or more sutures of the skull, which can be syndromic or isolated. Mutations in FGFR1, FGFR2, or FGFR3, among others, are often responsible for these syndromic cases. The associated of FGFR3 mutations with craniosynostosis has been restricted to three mutations, the common p.Pro250Arg in Muenke syndrome, p.Ala391Glu in Crouzon syndrome with acanthosis nigricans, and p.Pro250Leu identified in a family with isolated craniosynostosis. Other FGFR3 mutations result in various skeletal dysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia. Here, we report a novel mutation in exon 8 (IIIc) of FGFR3, p.Ala334Thr, in a young boy with mild craniosynostosis. The mutation segregated with mild craniosynostosis in the family and was absent in 188 normal controls. Alanine 334 is evolutionarily conserved in vertebrates and is located at the amino terminus of the βF loop in the FGFR3c isoform. The mutation is predicted to alter the protein tertiary structure which may impair its binding to its ligand, FGF1. The identification of a mutation in these clinically heterogeneous disorders can aid recurrence risk assessments. Although the implementation of a stepwise screening strategy is useful in diagnostics, mutations in unscreened regions of genes associated with craniosynostosis may explain a small proportion of craniosynostosis cases. © 2011 Wiley Periodicals, Inc.

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