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The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization.
J Clin Invest. 2009 Nov; 119(11):3462-72.JCI

Abstract

Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain-binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1A in COS-7 simian kidney cell line assays, suggesting that increased BMP pathway activity in COS-7 cells with R206H ACVR1 is due, at least in part, to decreased binding of this inhibitory factor. Consistent with these findings, in vivo analyses of zebrafish embryos showed BMP-independent hyperactivation of BMP signaling in response to the R206H mutant, resulting in increased embryonic ventralization. These data support the conclusion that the mutant R206H ACVR1 receptor in FOP patients is an activating mutation that induces BMP signaling in a BMP-independent and BMP-responsive manner to promote chondrogenesis, consistent with the ectopic endochondral bone formation in these patients.

Authors+Show Affiliations

Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6081, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19855136

Citation

Shen, Qi, et al. "The Fibrodysplasia Ossificans Progressiva R206H ACVR1 Mutation Activates BMP-independent Chondrogenesis and Zebrafish Embryo Ventralization." The Journal of Clinical Investigation, vol. 119, no. 11, 2009, pp. 3462-72.
Shen Q, Little SC, Xu M, et al. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009;119(11):3462-72.
Shen, Q., Little, S. C., Xu, M., Haupt, J., Ast, C., Katagiri, T., Mundlos, S., Seemann, P., Kaplan, F. S., Mullins, M. C., & Shore, E. M. (2009). The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. The Journal of Clinical Investigation, 119(11), 3462-72. https://doi.org/10.1172/JCI37412
Shen Q, et al. The Fibrodysplasia Ossificans Progressiva R206H ACVR1 Mutation Activates BMP-independent Chondrogenesis and Zebrafish Embryo Ventralization. J Clin Invest. 2009;119(11):3462-72. PubMed PMID: 19855136.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. AU - Shen,Qi, AU - Little,Shawn C, AU - Xu,Meiqi, AU - Haupt,Julia, AU - Ast,Cindy, AU - Katagiri,Takenobu, AU - Mundlos,Stefan, AU - Seemann,Petra, AU - Kaplan,Frederick S, AU - Mullins,Mary C, AU - Shore,Eileen M, Y1 - 2009/10/12/ PY - 2008/09/10/received PY - 2009/08/25/accepted PY - 2009/10/27/entrez PY - 2009/10/27/pubmed PY - 2009/11/18/medline SP - 3462 EP - 72 JF - The Journal of clinical investigation JO - J Clin Invest VL - 119 IS - 11 N2 - Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain-binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1A in COS-7 simian kidney cell line assays, suggesting that increased BMP pathway activity in COS-7 cells with R206H ACVR1 is due, at least in part, to decreased binding of this inhibitory factor. Consistent with these findings, in vivo analyses of zebrafish embryos showed BMP-independent hyperactivation of BMP signaling in response to the R206H mutant, resulting in increased embryonic ventralization. These data support the conclusion that the mutant R206H ACVR1 receptor in FOP patients is an activating mutation that induces BMP signaling in a BMP-independent and BMP-responsive manner to promote chondrogenesis, consistent with the ectopic endochondral bone formation in these patients. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/19855136/The_fibrodysplasia_ossificans_progressiva_R206H_ACVR1_mutation_activates_BMP_independent_chondrogenesis_and_zebrafish_embryo_ventralization_ L2 - https://doi.org/10.1172/JCI37412 DB - PRIME DP - Unbound Medicine ER -