Functional comparison of human ACVR1 and zebrafish Acvr1l FOP-associated variants in embryonic zebrafish

Background: Fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by progressive heterotopic ossification of muscle and connective tissues, is caused by autosomal dominant activating mutations in the type I receptor, ACVR1/ALK2. The classic human FOP variant, ACVR1^R206H , shows increased bone morphogenetic protein (BMP) signaling and activation by activins.

Results: Here, we performed in vivo functional characterization of human ACVR1^R206H and orthologous zebrafish Acvr1l^R203H using early embryonic zebrafish dorsoventral patterning as a phenotypic readout for receptor activity. Our results showed that human ACVR1^R206H and zebrafish Acvr1l^R203H exhibit functional differences in early embryonic zebrafish, and that human ACVR1^R206H retained its signaling activity in the absence of a ligand-binding domain (LBD). We also showed, for the first time, that zebrafish Acvr2ba/Acvr2bb receptors are required for human ACVR1^R206H signaling in early embryonic zebrafish.

Conclusions: Together, these data provide new insight into ACVR1^R206H signaling pathways that may facilitate the design of new and effective therapies for FOP patients.