Functional Testing of Bone Morphogenetic Protein (BMP) Pathway Variants Identified on Whole ‐Exome Sequencing in a Patient with Delayed‐Onset Fibrodysplasia Ossificans Progressiva (FOP) Using ACVR1R206H‐Specific Human Cellular and Zebrafish Models

ABSTRACTBone morphogenetic protein (BMP) signaling is critical in skeletal development. Overactivation can trigger heterotopic ossification (HO) as in fibrodysplasia ossificans progressiva (FOP), a rare, progressive disease of massive HO formation. A small subset of FOP patients harboring the causativeACVR1R206H mutation show strikingly mild or delayed-onset HO, suggesting that genetic variants in the BMP pathway could act as disease modifiers. Whole-exome sequencing of one such patient identifiedBMPR1AR443C andACVR2AV173I as candidate modifiers. Molecular modeling predicted significant structural perturbations. Neither variant decreased BMP signaling inACVR1R206H HEK 293T cells at baseline or after stimulation with BMP4 or activin A (AA), ligands that activate ACVR1R206H signaling. Overexpression ofBMPR1AR443C in aTg(ACVR1-R206Ha) embryonic zebrafish model, in which overactive BMP signaling yields ventralized embryos, did not alter ventralization severity, whileACVR2AV173I exacerbated ventralization. Co-expression of both variants did not affect dorsoventral patterning. In contrast,BMPR1A knockdown inACVR1R206H HEK cells decreased ligand-stimulated BMP signaling but did not affect dorsoventral patterning inTg(ACVR1-R206Ha) zebrafish.ACVR2A knockdown decreased only AA-stimulated signaling inACVR1R206H HEK cells and had no effect inTg(ACVR1-R206Ha) zebrafish. Co-knockdown inACVR1R206H HEK cells decreased basal and ligand-stimulated signaling, and co-knockdown/knockout (bmpr1aa...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Research Article Source Type: research