title: The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response.
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 ACVR1WTand ACVR1R206Hto different ligands. ACVR1WT, but not ACVR1R206Hinhibited 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 ACVR1WTand 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 ACVR1R206His 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.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Hildebrand
authors.affiliation: 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.
authors.forename: Katja
authors.initials: K
authors.lastname: Stange
authors.affiliation: 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Deichsel
authors.affiliation: 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.
authors.forename: Manfred
authors.initials: M
authors.lastname: Gossen
authors.affiliation: 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.
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D028341:Activins / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009221:Myositis Ossificans / Q000235:genetics*; D041681:NIH 3T3 Cells; D010012:Osteogenesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D008024:Ligands; D051785:Smad Proteins; C422405:activin A; D028341:Activins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D052005:Bone Morphogenetic Protein Receptors, Type I; D000469:Alkaline Phosphatase
keywords: Activin A; BMP; BMPR1A; BMPR1B; FOP