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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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).
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.
Combined multipoint lod plot for markers in the chromosome 2 FOP linkage region. (PDF 36 kb)
Amino acid homologies among human ACVR1 family members show conservation of the GS domain in human type I BMP/activin receptors. (PDF 33 kb)
ACVR1 primers for genomic DNA PCR amplification. (PDF 23 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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