What gene is involved in FOP?
The gene involved in FOP is ACVR1(1,2,3,4). This gene is located on the q arm of chromosome 2 between locations 23 and 24 (1). A single missense mutation causes FOP in the 206th amino acid (c.617 G>A; R206H) of the ACVR1 protein (4). ACVR1 encodes a transmembrane protein called activin A receptor type I (ACVR1) (1). ACVR1 is an integral component of BMP pathway by initiating signaling when bound to the ligand, ultimately causing downstream changes to initiate bone development (4). The mutation resides in the TGF-beta domain of the ACVR1 protein. In the pathological state, it is thought that the mutation perturbs normal signaling in soft tissue by making the inhibitor, FKBP12, unable to bind to the TGF-beta domain (5). The inability of the inhibitor to regulate the pathway in the absence of the proper signal confers the pathway to be “leaky” and facilitate signaling of bone growth in tissues that are not supposed to be forming bone. Ultimately, this aberrant signaling of the BMP pathway turns endothelial cells into mesenchymal stem cells and subsequently into bone through a process called endothelial-to-mesenchymal transition (6).
The gene involved in FOP is ACVR1(1,2,3,4). This gene is located on the q arm of chromosome 2 between locations 23 and 24 (1). A single missense mutation causes FOP in the 206th amino acid (c.617 G>A; R206H) of the ACVR1 protein (4). ACVR1 encodes a transmembrane protein called activin A receptor type I (ACVR1) (1). ACVR1 is an integral component of BMP pathway by initiating signaling when bound to the ligand, ultimately causing downstream changes to initiate bone development (4). The mutation resides in the TGF-beta domain of the ACVR1 protein. In the pathological state, it is thought that the mutation perturbs normal signaling in soft tissue by making the inhibitor, FKBP12, unable to bind to the TGF-beta domain (5). The inability of the inhibitor to regulate the pathway in the absence of the proper signal confers the pathway to be “leaky” and facilitate signaling of bone growth in tissues that are not supposed to be forming bone. Ultimately, this aberrant signaling of the BMP pathway turns endothelial cells into mesenchymal stem cells and subsequently into bone through a process called endothelial-to-mesenchymal transition (6).
Image Reference:
1. http://i2.cdn.turner.com/cnnnext/dam/assets/120522040338-dna-strand-illustration-double-helix-story-top.jpg
References:
1. "Fibrodysplasia Ossificans Progressiva." Genetics Home Reference. U.S. National Library of Medicine, 9 Feb. 2015. Web. 11 Feb. 2015. http://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva
2. Shore, E.M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525–527(2006). http://www.bio.davidson.edu/molecular/restricted/02bone/FOP_cause.pdf
3. Chakkalakal, S. A., Zhang, D., Culbert, A. L., Convente, M. R., Caron, R. J., Wright, A. C., Maidment, A. D. A., Kaplan, F. S. and Shore, E. M. (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J. Bone Miner. Res. 27, 1746-1756. http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/jbmr.1637/pdf
4. Kaplan, F. Fibrodysplasia ossificans progressiva: a blueprint for the metamorphosis. Annals of the New York Academy of Sciences, 2011, Vol.12371(1), pp.5-10. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502040/
1. http://i2.cdn.turner.com/cnnnext/dam/assets/120522040338-dna-strand-illustration-double-helix-story-top.jpg
References:
1. "Fibrodysplasia Ossificans Progressiva." Genetics Home Reference. U.S. National Library of Medicine, 9 Feb. 2015. Web. 11 Feb. 2015. http://ghr.nlm.nih.gov/condition/fibrodysplasia-ossificans-progressiva
2. Shore, E.M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525–527(2006). http://www.bio.davidson.edu/molecular/restricted/02bone/FOP_cause.pdf
3. Chakkalakal, S. A., Zhang, D., Culbert, A. L., Convente, M. R., Caron, R. J., Wright, A. C., Maidment, A. D. A., Kaplan, F. S. and Shore, E. M. (2012). An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J. Bone Miner. Res. 27, 1746-1756. http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/jbmr.1637/pdf
4. Kaplan, F. Fibrodysplasia ossificans progressiva: a blueprint for the metamorphosis. Annals of the New York Academy of Sciences, 2011, Vol.12371(1), pp.5-10. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502040/