Tags

Type your tag names separated by a space and hit enter

The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response.
Cell Signal. 2017 01; 29:23-30.CS

Abstract

Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common. In this study we compared the signalling responses of ACVR1WT and ACVR1R206H to different ligands. ACVR1WT, but not ACVR1R206H inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1WT, but enhanced by ACVR1R206H. In comparison, BMP6 or BMP7 activated ACVR1WT and caused a hyper-activation of ACVR1R206H. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1R206H. We conclude that the FOP mutation ACVR1R206H is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients.

Authors+Show Affiliations

Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany. Electronic address: laura.hildebrand@charite.de.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany; Leibniz Institute for Farm Animal Biology, Institute for Muscle Biology and Growth, Dummerstorf, Germany. Electronic address: stange.katja@fbn-dummerstorf.de.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany. Electronic address: alexandra.deichsel@gmail.com.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht, Teltow, Germany. Electronic address: manfred.gossen@charite.de.Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Virchow Campus, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany. Electronic address: petra.seemann@charite.de.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27713089

Citation

Hildebrand, Laura, et al. "The Fibrodysplasia Ossificans Progressiva (FOP) Mutation p.R206H in ACVR1 Confers an Altered Ligand Response." Cellular Signalling, vol. 29, 2017, pp. 23-30.
Hildebrand L, Stange K, Deichsel A, et al. The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response. Cell Signal. 2017;29:23-30.
Hildebrand, L., Stange, K., Deichsel, A., Gossen, M., & Seemann, P. (2017). The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response. Cellular Signalling, 29, 23-30. https://doi.org/10.1016/j.cellsig.2016.10.001
Hildebrand L, et al. The Fibrodysplasia Ossificans Progressiva (FOP) Mutation p.R206H in ACVR1 Confers an Altered Ligand Response. Cell Signal. 2017;29:23-30. PubMed PMID: 27713089.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response. AU - Hildebrand,Laura, AU - Stange,Katja, AU - Deichsel,Alexandra, AU - Gossen,Manfred, AU - Seemann,Petra, Y1 - 2016/10/04/ PY - 2016/07/04/received PY - 2016/09/23/revised PY - 2016/10/02/accepted PY - 2016/11/5/pubmed PY - 2017/11/29/medline PY - 2016/11/7/entrez KW - Activin A KW - BMP KW - BMPR1A KW - BMPR1B KW - FOP SP - 23 EP - 30 JF - Cellular signalling JO - Cell Signal VL - 29 N2 - Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common. In this study we compared the signalling responses of ACVR1WT and ACVR1R206H to different ligands. ACVR1WT, but not ACVR1R206H inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1WT, but enhanced by ACVR1R206H. In comparison, BMP6 or BMP7 activated ACVR1WT and caused a hyper-activation of ACVR1R206H. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1R206H. We conclude that the FOP mutation ACVR1R206H is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/27713089/The_Fibrodysplasia_Ossificans_Progressiva__FOP__mutation_p_R206H_in_ACVR1_confers_an_altered_ligand_response_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(16)30237-6 DB - PRIME DP - Unbound Medicine ER -