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 ACVR1^R206H -Specific Human Cellular and Zebrafish Models.

ABSTRACT: Bone 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 causative ACVR1^R206H 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 identified BMPR1A^R443C and ACVR2A^V173I as candidate modifiers. Molecular modeling predicted significant structural perturbations. Neither variant decreased BMP signaling in ACVR1^R206H HEK 293T cells at baseline or after stimulation with BMP4 or activin A (AA), ligands th

SUBMITTER: Wentworth KL 

PROVIDER: S-EPMC9950781 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature