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 ACVR1^WT and ACVR1^R206H to different ligands. ACVR1^WT, but not ACVR1^R206H 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 ACVR1^WT, but enhanced by ACVR1^R206H. In comparison, BMP6 or BMP7 activated ACVR1^WT and caused a hyper-activation of ACVR1^R206H. 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 ACVR1^R206H. We conclude that the FOP mutation ACVR1^R206H 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.

Keywords: Activin A; BMP; BMPR1A; BMPR1B; FOP.