Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1

Authors

  • Frederick S. Kaplan,

    1. Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    2. Department of Medicine, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    3. Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Meiqi Xu,

    1. Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    2. Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Petra Seemann,

    1. Max Planck Institute for Molecular Genetics, Research Group Development and Disease, Berlin, Germany
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  • J. Michael Connor,

    1. Duncan Guthrie Institute of Medical Genetics; University of Glasgow Medical School, Glasgow, Scotland
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  • David L. Glaser,

    1. Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    2. Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Liam Carroll,

    1. Mid-Western Regional Hospital, Dooradoyle, Limerick, Ireland
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  • Patricia Delai,

    1. Department of Orthopaedic Surgery, Santa Casa de Misericórdía de São Paulo School of Medicine, São Paulo-SP, Brazil
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  • Elisabeth Fastnacht-Urban,

    1. Department of Radiology, KinderKlinik, Klinikum Lüdenscheid, Lüdenscheid, Germany
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  • Stephen J. Forman,

    1. Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California
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  • Gabriele Gillessen-Kaesbach,

    1. Institut für Humangenetik Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
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  • Julie Hoover-Fong,

    1. Greenberg Center for Skeletal Dysplasia, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Bernhard Köster,

    1. Department of Pediatrics, KinderKlinik, Klinikum Lüdenscheid, Lüdenscheid, Germany
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  • Richard M. Pauli,

    1. Department of Pediatrics, University of Wisconsin-Madison, Clinical Genetics Center, Madison, Wisconsin
    2. Department of Medical Genetics, University of Wisconsin-Madison, Clinical Genetics Center, Madison, Wisconsin
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  • William Reardon,

    1. National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland
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  • Syed-Adeel Zaidi,

    1. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
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  • Michael Zasloff,

    1. Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    2. Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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  • Rolf Morhart,

    1. Department of Pediatrics, Medizin Klinikum, Garmisch-Partenkirchen, Germany
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  • Stefan Mundlos,

    1. Max Planck Institute for Molecular Genetics, Research Group Development and Disease, Berlin, Germany
    2. Institute für Medizinische Genetik, Charité-Universitäts-medizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
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  • Jay Groppe,

    1. Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas
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  • Eileen M. Shore

    Corresponding author
    1. Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    2. Department of Genetics, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    3. Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
    • University of Pennsylvania, Department of Orthopaedic Surgery, 424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6081
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  • Communicated by Peter Byers

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development. Hum Mutat 0, 1–12, 2008. © 2008 Wiley-Liss, Inc.

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