Author: Andrew Rice
FOP can often be identified at birth, and this diagnosis is often made through your big toes. The big toes of a baby born with FOP are misshapen, bent inwards and fairly short. This is the most obvious way to tell if a baby has FOP, but other methods of diagnosis include deformities in the ears. FOP can also be diagnosed genetically, though this discovery is relatively recent in the history of FOP.
All living things that we know of use DNA to encode the information that is used to ‘build’ themselves. Many diseases are caused by mutations, or irregular changes, in this genetic code. These diseases are referred to as genetic diseases, and can be either inherited through your parents’ DNA or through a spontaneous mutation in your own DNA early in life. These changes, even if small, can have incredible consequences in the living organism they affect.
FOP itself is a genetic disease. The gene, or segment of DNA, of interest is called the ACVR1 gene. This segment of DNA encodes the information to build a protein, the Activin A receptor type 1, that acts as a cellular receptor. This protein is involved in a signaling pathway, or a sequence of small molecules that each signal each other to generate a desired response in the body. Through a sequence of these small molecules, the protein built from the ACVR1 gene is critically involved in the generation of the skeleton during development before birth. Many animals, from reptiles to birds to humans, use this signaling pathway to create the body’s skeleton.
In FOP, the ACVR1 gene is mutated. Proteins are made up of amino acids, and the mutated version of ACVR1 builds a version of the Activin A receptor that is ever so slightly different from the normal version. The FOP version of this protein uses the amino acid histidine rather than the amino acid arginine in the 206th position of the protein (proteins can be made up of many amino acids!). While changing one amino acid out of more than 206 might seem like a small change, it drastically alters the function of the protein and the signaling pathway as a whole.
A small molecule must interact with the Activin A receptor to activate it and cause the signaling pathway that forms bones to commence. This often doesn’t occur after birth, as the body has all of the bones it needs. The mutated version of the Activin A receptor, however, binds it’s activating small molecule more often. The mutated version of the protein can also be activated by other molecules. Most importantly, these new activators of the receptor are brought near the receptor during the inflammation response, the body’s response to damage. This explains why injury, and the inflammation that comes with it, can cause overactivity in this receptor, a flare-up of FOP, and the formation of new bone. You can learn more about this signaling pathway in detail here.
Studying FOP itself has been quite difficult. Scientists usually study cultured human cells to understand this disease, but they have also used mouse, fly, and zebrafish models. These animals have allowed us to understand a lot about this disease, from the exact cause of bone formation to our understanding of what types of molecules can activate the Activin A receptor. To treat this disease, we will inevitably need to understand which types of molecules can activate this receptor before we are able to inhibit its activation. Currently, the drug Palovarotene is our best strategy. This drug, currently in stage 3 of its clinical trials, works by upregulating retinoid signaling Model organisms helped us understand that a decrease in retinoid signaling is essential for the bone formation characteristic of FOP. By upregulating retinoid signaling, we are able to stop bone formation in FOP.
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