Affiliation:
1. 1 grid.4488.0 0000 0001 2111 7257 Department of Medicine III & Center for Healthy Aging Technische Universität Dresden 01307 Dresden Germany
2. 2 grid.8379.5 0000 0001 1958 8658 Department of Orthopedics University of Würzburg Würzburg Germany
3. 3 grid.25879.31 0000 0004 1936 8972 Departments of Orthopedics and Genetics, Perelman School of Medicine University of Pennsylvania Philadelphia USA
Abstract
Abstract
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant genetic condition characterised by progressive extra-skeletal bone formation in connective tissues. Over time, heterotopic ossification entombs patients within a second skeleton, drastically impairing their mobility and autonomy. Mutations in the ACVR1 gene have been identified as the cause of FOP. The single nucleotide missense mutation in ACVR1, c.617G > A, causes a single amino acid substitution, p.R206H, and is found in >90% of all patients. Heterotopic bone formation in FOP mimics embryonic skeletal endochondral ossification, with cartilage forming after fibroproliferative tissue condensation as an intermediate stage prior to osteogenesis and tissue ossification. In contrast to normal embryonic endochondral ossification, heterotopic ossification in FOP involves an inflammatory phase that precedes cartilage and bone formation. New insights into the mechanisms of action of heterotopic bone formation in FOP have led to the discovery of new potential treatment targets including inhibitors of BMP signalling, activin A inhibitors, and mTOR inhibitors. This review summarises the current knowledge on mutations causing FOP, as well as the molecular basis of heterotopic ossification and the therapeutic options that result from these discoveries.
Subject
Genetics (clinical),Genetics
Cited by
3 articles.
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