ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

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Science Translational Medicine  02 Sep 2015:
Vol. 7, Issue 303, pp. 303ra137
DOI: 10.1126/scitranslmed.aac4358

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Explaining bone overgrowth

Fibrodysplasia ossificans progressiva (FOP) is a rare, but deadly, genetic condition that causes growth of bony structures in place of normally soft tissues such as muscle and ligaments. The causal mutation, in the bone morphogenetic protein receptor ACVR1, has been thought to boost the receptor’s activity, triggering inappropriate bone formation. Hatsell et al. suggest that it works instead by a different mode of action—acquiring the ability to respond to the injury-related factor activin, which may explain some of the puzzling aspects of the disease.

The mutated ACVR1 receptor, expressed in cultured cells, responded to activin as well as to its natural ligand, bone morphogenetic protein. When the mutated gene was engineered to be expressed in adult mice (to avoid its perinatal lethal effects), the animals developed heterotopic ossification, as in FOP. Unexpectedly, for heterotypic ossification, the receptor required stimulation by the endogenous ligand activin. Small sponges soaked with activin ossified after they were implanted into the animals. Normally, activin blocks binding of the ACVR1 receptor by its natural ligand bone morphogenetic protein-2.

Finally, the authors confirmed that activin A is a potential therapeutic target for the treatment of FOP: Animals carrying the mutated receptor that were also treated with a monoclonal antibody to activin A did not show heterotopic ossification, even as long as 6 weeks after introduction of the mutation. A mutation-induced ligand specificity change is an unusual cause of disease, but this mechanism may explain why the ossification in FOP patients is triggered by injury or trauma to tissues—a situation that induces high concentrations of activin.


Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1R206H) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1R206H mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1R206H causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.

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