Dysregulation of the BMP-4 signaling pathway in fibrodysplasia ossificans progressiva

Identification of gene mutations in Mendelian disorders is often determined by linkage analysis and positional cloning, an approach that is difficult for fibrodysplasia ossificans progressiva (FOP) due to a low reproductive fitness that results in a small number of multigenerational families showing inheritance of the disease. Altered signaling pathways can be investigated as a complementary method to identify the consequences of the mutated gene responsible for FOP and to identify potential therapeutic targets. Candidate signaling pathways for FOP are those that malfunctioning could account for the malformation of the great toes during embryonic development and could explain the postnatal progressive heterotopic endochondral ossification. Signaling pathways that fit these criteria are the BMP signaling pathway and its interacting pathways. A large body of data suggest that the BMP-4 signaling pathway is dysregulated in FOP.