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

Shore, Eileen M.<sup>1,2,3</sup>; Xu, Meiqi<sup>1,2</sup>; Feldman, George J.<sup>1,2</sup>; Fenstermacher, David A.<sup>4,5,6</sup>; Cho, Tae-Joon<sup>7</sup>; Choi, In Ho<sup>7</sup>; Connor, J. Michael<sup>8</sup>; Delai, Patricia<sup>9</sup>; Glaser, David L.<sup>1,2</sup>; LeMerrer, Martine<sup>10</sup>; Morhart, Rolf<sup>11</sup>; Rogers, John G.<sup>12</sup>; Smith, Roger<sup>13</sup>; Triffitt, James T.<sup>14</sup>; Urtizberea, J. Andoni<sup>15</sup>; Zasloff, Michael<sup>1,2,16,17</sup>; Brown, Matthew A.<sup>14,18</sup>; Kaplan, Frederick S.<sup>1,2,19</sup>

Affiliations

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

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

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

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

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

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

⁷Department 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

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

⁹Department 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

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

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

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

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

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

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

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

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

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

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

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.

Links

DOI: 10.1038/ng1783

PubMed: 16642017

WoS: 000237147500012

History

Received: 2005-12-22

Accepted: 2006-03-15

Online: 2006-04-23

Cited By (36)

Year	Entry
2020	Towler OW, Shore EM, Kaplan FS. Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva. Bone. January 2020;130:115116.
2020	Pignolo RJ, Cheung K, Kile S, Fitzpatrick MA, De Cunto C, Al Mukaddam M, Hsiao EC, Baujat G, Delai P, Eekhoff EMW, Di Rocco M, Grunwald Z, Haga N, Keen R, Levi B, Morhart R, Scott C, Sherman A, Zhang K, Kaplan FS. Self-reported baseline phenotypes from the international fibrodysplasia ossificans progressiva (fop) association global registry. Bone. May 2020;134:115274.
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2020	Matsuoka M, Tsukamoto S, Orihara Y, Kawamura R, Kuratani M, Haga N, Ikebuchi K, Katagiri T. Design of primers for direct sequencing of nine coding exons in the human ACVR1 gene. Bone. September 2020;138:115469.
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2020	Strong AL, Spreadborough PJ, Pagani CA, Haskins RM, Dey D, Grimm PD, Kaneko K, Marini S, Huber AK, Hwang C, Westover K, Mishina Y, Bradley MJ, Levi B, Davis TA. Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma. Bone. October 2020;139:115517.
2020	Kaplan FS, Al Mukaddam M, Stanley A, Towler OW, Shore EM. Fibrodysplasia ossificans progressiva (FOP): a disorder of osteochondrogenesis. Bone. November 2020;140:115539.
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2020	Gregson CL, Bergen DJM, Leo P, Sessions RB, Wheeler L, Hartley A, Youlten S, Croucher PI, McInerney‐Leo AM, Fraser W, Tang JCY, Anderson L, Marshall M, Sergot L, Paternoster L, Smith GD, Brown MA, Hammond C, Kemp JP, Tobias JH, Duncan EL; The AOGC Consortium. A rare mutation in SMAD9 associated with high bone mass identifies the SMAD‐dependent BMP signaling pathway as a potential anabolic target for osteoporosis. J Bone Miner Res. January 2020;35(1):92-105.
2020	Eisner C, Cummings M, Johnston G, Tung LW, Groppa E, Chang C, Rossi FMV. Murine tissue‐resident PDGFRΑ+ fibro‐adipogenic progenitors spontaneously acquire osteogenic phenotype in an altered inflammatory environment. J Bone Miner Res. August 2020;35(8):1525-1534.
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2022	Wang H, Zhang Q, Kaplan FS, Pignolo RJ. Clearance of senescent cells from injured muscle abrogates heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva. J Bone Miner Res. January 2022;37(1):95-107.
2022	Pignolo RJ, McCarrick-Walmsley R, Wang H, Qiu S, Hunter J, Barr S, He K, Zhang H, Kaplan FS. Plasma-soluble biomarkers for fibrodysplasia ossificans progressiva (FOP) reflect acute and chronic inflammatory states. J Bone Miner Res. March 2022;37(3):475-483.
2022	Pignolo RJ, Baujat G, Hsiao EC, Keen R, Wilson A, Packman J, Strahs AL, Grogan DR, Kaplan FS. Palovarotene for fibrodysplasia ossificans progressiva (FOP): results of a randomized, placebo-controlled, double-blind phase 2 trial. J Bone Miner Res. October 2022;37(10):1891-1902.
2022	Forlino A. Shedding light on bone morphogenetic protein (BMP) signaling modifiers to modulate fibrodysplasia ossificans progressiva severity. J Bone Miner Res. November 2022;37(11):2055-2057.
2022	Wentworth KL, Lalonde RL, Groppe JC, Brewer N, Moody T, Hansberry S, Taylor KE, Shore EM, Kaplan FS, Pignolo RJ, Yelick PC, Hsiao EC. Functional testing of bone morphogenetic protein (BMP) pathway variants identified on whole-exome sequencing in a patient with delayed-onset fibrodysplasia ossificans progressiva (FOP) using ACVR1^R206H-specific human cellular and zebrafish models. J Bone Miner Res. November 2022;37(11):2058-2076.
2022	Yamamoto M, Stoessel SJ, Yamamoto S, Goldhamer DJ. Overexpression of wild-type ACVR1 in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification. J Bone Miner Res. November 2022;37(11):2077-2093.
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2023	Allen RS, Jones WD, Hale M, Warder BN, Shore EM, Mullins MC. Reduced GS domain serine/threonine requirements of fibrodysplasia ossificans progressiva mutant Type I BMP receptor ACVR1 in the zebrafish. J Bone Miner Res. September 2023;38(9):1364-1385.
2016	Salazar VS, Gamer LW, Rosen V. BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol. April 2016;12(4):203-221.
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