Molecular Bases of the Disease State

A single mutation, R206H, in the previously mentioned GS domain of ACVR1 is responsible for FOP (Pacifici and Shore 2016).  The ACVR1 protein is made of amino acids. One of those amino acids, arginine (R) 206, has been replaced by a histidine (H). The R206 mutation is universal in FOP, but it is not the only one that can occur (Haupt et al 2014). The instances of non-R206 mutations are rare in an already rare disease, so we will not focus on them here. A few other peripheral mutations in other regions of the genome are also associated with FOP symptoms, but they are not as well conserved or well studied as the R206H mutation (Martelli and Santos 2014, Pacifici and Shore 2016). Some of these other mutations occur in the BMP4 gene (Martelli and Santos 2014). These mutations may explain the unusually high levels of BMP4 present in FOP patients (Martelli and Santos 2014).

 

Arginine. Source: Wikipedia
Arginine. Source: Wikipedia

 

Histidine. Source: Sigma Aldrich
Histidine. Source: Sigma Aldrich

The FOP mutation is a gain-of-function mutation (Pacifici and Shore 2016). This means that the protein is now able to do something that it could not do before. In the case of FOP, ACVR1 becomes highly active. As mentioned above, high levels of BMP4 are found in FOP patients. BMP4 is a bone morphogenetic protein that binds to the receptor complex that includes ACVR1. So, in FOP ACVR1 is not only hyperactive, but also has access to large amounts of the ligand that binds it to start the signaling pathway that leads to bone growth. Interestingly, it has been demonstrated that the mutation in ACVR1 is sufficient to trigger the signaling pathway even in the absence of a BMP ligand (Shen et al 2009).

Overview of FOP. Source:
Overview of FOP. Source: Pacifici and Shore 2016

Another interesting effect of the R206H mutation is how it alters the ability of ACVR1 to bind to the inhibitor FKBP12 (Shen et al 2009). FKBP12’s role is as an inhibitory agent to prevent ACVR1 from signaling Smad proteins in the absence of a BMP. However, in the mutant ACVR1 appears to have a reduced affinity for FKBP12 (Shen et al 2009). The R206H mutation, while at first seeming so small, can have such devastating effects on cellular metabolism. With that mutation you now have a protein that is hypersensitive to its ligand and has a reduced binding capability with its inhibitor. In addition, not only can it activate Smad proteins without first binding a BMP, but there is also an increased presence of BMP4 for good measure. Essentially everything that could happen to cause the body to produce extraneous bone is happening.