What is Fibrodysplasia Ossificans Progressiva?
Fibrodysplasia Ossificans Progressiva (FOP) is an extremely rare genetic condition that results in extraneous bone formation in soft tissue such as muscles (Martelli and Santos 2014). The condition begins to present in infancy. Patients typically have very short, deformed big toes (Al Kaissi et al. 2016). As the diseases progresses in early childhood, patients tend to develop painful nodules under the skin (Al Kaissi et al. 2016). As the disease advances, connective tissues ossify, or become bone (Martelli and Santos 2014). Eventually, joints become locked in place and the affected individual is slowly frozen by the progress of the bone formation (Figure 1). Another interesting aspect of FOP is that when an afflicted person’s tissue is damaged, the injury is ‘healed’ with more bone formation (Martelli and Santos 2014). Due to this phenomenon, surgery is not a viable way to treat the disease.
How do you get FOP?
FOP is an autosomal dominant genetic disorder (Martelli and Santos 2014). This means that FOP can be inherited from a parent, but in this case is most often caused by a mutation in your DNA during fetal development. FOP is caused by a very specific mutation. On chromosome 2, there is a gene called ACVR1 (Feldman et al. 2000). In FOP, there is a point mutation on this gene, a single DNA base is altered. ACVR1 codes for a protein called ACVR1 (also known as ALK2). Proteins are made up of amino acids. In this particular protein, due to the DNA mutation, the amino acid arginine at the 206 position has been replaced by a histidine. This R206H mutation, as it is known, is responsible for FOP.
How does a single mutation cause so much damage?
The protein ACVR1 that is mutated in FOP is a type I bone morphogenetic protein (BMP) receptor (Pacifici and Shore 2016). This means it is involved in the regulation of bone formation. Mesenchymal cells are a type of cell that can become bone-forming cells when signaled to by BMPs (Martelli and Santos 2014). Signaling BMP molecules typically bind to ACVR1 as part of a complex that ultimately tells certain cells to differentiate to bone forming cells. Several factors have been found to contribute to the hyperactivation of this pathway. In FOP, the signaling molecule BMP-4 is found in very high levels. The complex that accepts BMP receptors and contains ACVR1 is present on the surface of the cell when it should have been internalized, or made unavailable to BMPs (de la Peña et al. 2005). There is also a protein that inhibits the activity of ACVR1, but it binds more loosely to the mutated version of the protein (Shen et al. 2009). All of these factors combine to form a hyper-active pathway that leads to abnormal, destructive bone formation.
What don’t we know about FOP?
The mutation that causes FOP and the pathway it disrupts have been well documented, but there is still more to be learned. Flare-ups of bone formation can occur as a result of trauma or spontaneously. Neither mechanism is particularly well understood at the moment. Additionally, there is no cure for this condition. Treatments are being developed, but there is a long way to go.