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A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

Nature Genetics volume 38, pages 525–527 (2006)Cite this article

A Corrigendum to this article was published on 01 February 2007

This article has been updated

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G → A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

NOTE: In the version of this article initially published, several contributing authors were listed collectively under the name The International FOP Research Consortium. In order to facilitate the electronic citation of author contributions, the authors have chosen to delete the Consortium name and replace it with the names of the individual consortium authors in alphabetical order. This error has been corrected in the HTML and PDF versions of the article.

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Figure 1: Characteristic clinical features of FOP and linkage mapping in five pedigrees.
Figure 2: R206H mutations in ACVR1 cause FOP.

Change history

  • 31 December 2006

    NOTE: In the version of this article initially published, several contributing authors were listed collectively under the name The International FOP Research Consortium. In order to facilitate the electronic citation of author contributions, the authors have chosen to delete the Consortium name and replace it with the names of the individual consortium authors in alphabetical order. This error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank the individuals and families with FOP for providing tissue samples for these studies and for their courage and faith; J. Peeper and A. Cali for their inspiration and leadership of the international FOP community; many colleagues for discussions over the course of these investigations and many physicians worldwide who referred patients and helped in sending tissue samples. We acknowledge the contributions of R. Pignolo, University of Pennsylvania School of Medicine; M. Fardeau, Institut de Myologie, Hôpital de la Salpetriere; D. Baldwin, University of Pennsylvania Microarray Core Facility; G. Abecasis, University of Michigan, for linkage data analysis advice; C. Street, University of Pennsylvania Biomedical Informatics Facility; University of Pennsylvania School of Medicine DNA Sequencing Facility and the University of Utah School of Medicine Genomics Core Facility. We thank V. Cheung for discussion of the manuscript, M. Liljesthröm for her observations and the people of Santa Maria and many other communities around the globe for their faith and generosity over many years. We also thank the many present and past members of our laboratory for their dedication and technical support, particularly those who have participated in candidate gene screening, especially A. Strong, H. Yang and P. Chen. This work was supported by endowments from the Cali and Weldon families and their associates and friends, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, the Roemex and Grampian Fellowships, the Stephen Roach-Whitney Weldon Fellowship and grants from the International Fibrodysplasia Ossificans Progressiva Association (http://www.ifopa.org), Association Pierre-Yves, FOPe.v., University of Oxford FOP Research Fund, the Sarah Cameron Fund, and the US National Institutes of Health (NIH R01-AR41916).

Author information

Authors and Affiliations

  1. Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Eileen M Shore, Meiqi Xu, George J Feldman, David L Glaser, Michael Zasloff & Frederick S Kaplan

  2. Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Eileen M Shore, Meiqi Xu, George J Feldman, David L Glaser, Michael Zasloff & Frederick S Kaplan

  3. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Eileen M Shore

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    David A Fenstermacher

  5. Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    David A Fenstermacher

  6. Biomedical Informatics Facility, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    David A Fenstermacher

  7. Department of Orthopaedic Surgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, 28 Yeongeon-dong, Jongno-gu, Seoul, 110-744, Republic of Korea

    Tae-Joon Cho & In Ho Choi

  8. Division of Developmental Medicine, Institute of Medical Genetics, University of Glasgow Medical School, Yorkhill Academic Campus, Glasgow , G3 8SJ, Scotland, UK

    J Michael Connor

  9. Department of Orthopaedic Surgery, Santa Casa de Misericórdia de São Paulo School of Medicine, Rua Dr. Cesário Motta Jr. 112, Cep: 01221-020, São Paulo, Brazil

    Patricia Delai

  10. Department of Genetics, Hôpital Necker-Enfants Malades, INSERM U-781, 149 Rue de Sèvres, Paris, 75015, France

    Martine LeMerrer

  11. Department of Pediatrics, Klinikum Garmisch-Partenkirchen GmbH, Garmisch-Partenkirchen, D-82467, Germany

    Rolf Morhart

  12. Department of Genetics, Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, Australia

    John G Rogers

  13. Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford, OX3 7LD, UK

    Roger Smith

  14. Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Oxford, OX3 7LD, UK

    James T Triffitt & Matthew A Brown

  15. Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Marin, Hendaye, 64700, France

    J Andoni Urtizberea

  16. Department of Surgery, Georgetown University School of Medicine, Washington, 20057, DC, USA

    Michael Zasloff

  17. Department of Pediatrics, Georgetown University School of Medicine, Washington, 20057, DC, USA

    Michael Zasloff

  18. Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, 4102, Queensland, Australia

    Matthew A Brown

  19. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Frederick S Kaplan

Authors
  1. Eileen M Shore
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  2. Meiqi Xu
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  6. In Ho Choi
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  7. J Michael Connor
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  8. Patricia Delai
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  9. David L Glaser
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  10. Martine LeMerrer
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  14. James T Triffitt
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  15. J Andoni Urtizberea
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  16. Michael Zasloff
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  17. Matthew A Brown
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  18. Frederick S Kaplan
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Corresponding authors

Correspondence to Eileen M Shore or Frederick S Kaplan.

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Competing interests

F.S.K. and E.M.S. have submitted a patent application for the information contained in this manuscript. However, they have waived all their rights to shares of any net royalty income and will derive no personal financial gain from this patent. The other authors declare that they have no financial conflicts of interest.

Supplementary information

Supplementary Fig. 1

Combined multipoint lod plot for markers in the chromosome 2 FOP linkage region. (PDF 36 kb)

Supplementary Fig. 2

Amino acid homologies among human ACVR1 family members show conservation of the GS domain in human type I BMP/activin receptors. (PDF 33 kb)

Supplementary Table 1

ACVR1 primers for genomic DNA PCR amplification. (PDF 23 kb)

Supplementary Methods (PDF 41 kb)

Supplementary Note (PDF 53 kb)

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Shore, E., Xu, M., Feldman, G. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38, 525–527 (2006). https://doi.org/10.1038/ng1783

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