This web page was produced as an assignment for genetics 564, an undergraduate course at UW-Madison
What is Fibrodysplasia Ossificans Progressiva?
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by the progressive induction of postnatal heterotopic ossifications (1). Although the onset is variable, additional bone formation tends to arise in the first decade of life (2). Moreover, soft tissue at extra-skeletal sites such as the skeletal muscles, tendons, ligaments, fascia and aponeuroses can be transformed into bone, thus, result in gradual and irreversible immobility (3,4). FOP is present in approximately one in two million people (5). Besides the heterotopic bone formation, another clinical feature that often accompanies FOP in 95 percent of patients is malformations in the great toe (2). Flare-ups of accelerated bone formation often occur during childhood and can be spontaneous or a result of a soft tissue injury such as surgery, intramuscular immunizations, viral infections, dental procedures or even a bump (4,6). These painful flare-ups result in the permanent formation of a second skeleton and can fuse joints together, therefore restraining movement at that site (7). A missense mutation in a single gene called the ACVR1, which encodes the activin A receptor type I is responsible for FOP. The activin A receptor protein is an integral protein in the bone morphogenetic pathway (2,3,4,7). Activin A receptor proteins reside in the cell membrane and receive and transmit signals in the BMP pathway resulting in gene expression changes that form bone growth(7).
The ACVR1 Gene
A missense mutation (c.617G>A; R206H) in the ACVR1 gene on chromosome two (2q23-q24) is the most common cause for FOP (1, 4, 5, 6). This single missense mutation results in the 206th arginine amino acid to be swapped out for a histidine during translation (3, 4). This modification in the assembly of the peptide results in a conformational change in the activin A receptor type I protein TGF-beta domain (3,4,7). This domain is responsible for receiving signals from the outside of the cell and initiating the receptor to catalyze the BMP signaling pathway that ultimately expresses genes associated with producing cartilage and bone. This protein is imperative due to the fact it resides in the cell membrane and permits the change in cellular function from external signaling (1, 3, 4 7). Under normal circumstances, this protein is only activated by its corresponding ligand. A protein called FKBP12 inhibits the activation of activin A receptors, which enables regulation of signaling and prevents an inappropriate signal in the absence of the ligand. By various protein modeling studies, it is thought this single amino acid change in the 206th amino acid hinders the binding of the inhibitor FKBP12 and thus, gives the cell unchecked activation and causes it to be constitutively active (1,3,7). Consequently, this alteration of signaling facilitates the overgrowth of bone in FOP.
Symptoms
With the exception of monophalangism and other digital malformations present in most FOP patients at birth, babies with FOP do not exhibit telltale heterotopic ossifications (3). Usually, symptoms of bone growth start to manifest themselves within the first decade of life (5). Disease onset can be spontaneous or triggered by soft tissue damage. Swelling, pain and flare-ups of bone growth can be initiated by surgery, immunizations, soft tissue trauma, viral infections, dental procedures or even a bump (2, 3, 4, 6). Areas of the body that tend to manifest the ossifications first are the dorsal, axial, cranial and proximal areas of the body while subsequently, the ventral, appendicular, caudal and distal areas tend to transform later (1). Once an area undergoes the metamorphosis into bone, it is irreversible and permanently constrains mobility in these areas. Luckily, smooth muscle and cardiac muscle are exempt from being affected by this disease. Additionally, the tongue and diaphragm are not commonly affected either (2,6). Given the nature of which flare-ups occur, there is no surgical procedure to remove of newly developed bone. Surgery and tissue damage provoke further ossification therefore no surgical removal of bone can be done (2). An excerpt of one of the first documented accounts of FOP can be read below. This observation was written by surgeon John Freke in 1740:
"April 14, 1736. There came a boy of healthy look and 14 years of age, to ask of us at The Hospital, what should be done to
cure him of many large swellings on his back which began about three years since, and have continued to grow as large on
many parts as a penny-loaf, particularly on the left side. They arise from all the vertebre of the neck, and reach down to the
sacrum. They likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of coral do, they make, as it were, a fixed bony pair of bodice (1)."
By virtue of the rarity of FOP, the bony formations present on the spine and back are often misdiagnosed as juvenile fibromatosis (extra-abdominal desmoid tumors), fibrosacroma, chondrosarcoma, osteosarcoma, cephalohematoma or lymphedema (2). Misdiagnoses of FOP can result in unnecessary biopsies that further perpetuate the bone growth and worsen the condition (2). There is no known treatment or preventative measure for FOP at this time. The average life span of a patient with FOP is 45 years of age, however, it is recorded that some patients with FOP can live into their seventies (2). Despite this, researchers are trying to find mechanisms to understand and eventually control this puzzling affliction.
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by the progressive induction of postnatal heterotopic ossifications (1). Although the onset is variable, additional bone formation tends to arise in the first decade of life (2). Moreover, soft tissue at extra-skeletal sites such as the skeletal muscles, tendons, ligaments, fascia and aponeuroses can be transformed into bone, thus, result in gradual and irreversible immobility (3,4). FOP is present in approximately one in two million people (5). Besides the heterotopic bone formation, another clinical feature that often accompanies FOP in 95 percent of patients is malformations in the great toe (2). Flare-ups of accelerated bone formation often occur during childhood and can be spontaneous or a result of a soft tissue injury such as surgery, intramuscular immunizations, viral infections, dental procedures or even a bump (4,6). These painful flare-ups result in the permanent formation of a second skeleton and can fuse joints together, therefore restraining movement at that site (7). A missense mutation in a single gene called the ACVR1, which encodes the activin A receptor type I is responsible for FOP. The activin A receptor protein is an integral protein in the bone morphogenetic pathway (2,3,4,7). Activin A receptor proteins reside in the cell membrane and receive and transmit signals in the BMP pathway resulting in gene expression changes that form bone growth(7).
The ACVR1 Gene
A missense mutation (c.617G>A; R206H) in the ACVR1 gene on chromosome two (2q23-q24) is the most common cause for FOP (1, 4, 5, 6). This single missense mutation results in the 206th arginine amino acid to be swapped out for a histidine during translation (3, 4). This modification in the assembly of the peptide results in a conformational change in the activin A receptor type I protein TGF-beta domain (3,4,7). This domain is responsible for receiving signals from the outside of the cell and initiating the receptor to catalyze the BMP signaling pathway that ultimately expresses genes associated with producing cartilage and bone. This protein is imperative due to the fact it resides in the cell membrane and permits the change in cellular function from external signaling (1, 3, 4 7). Under normal circumstances, this protein is only activated by its corresponding ligand. A protein called FKBP12 inhibits the activation of activin A receptors, which enables regulation of signaling and prevents an inappropriate signal in the absence of the ligand. By various protein modeling studies, it is thought this single amino acid change in the 206th amino acid hinders the binding of the inhibitor FKBP12 and thus, gives the cell unchecked activation and causes it to be constitutively active (1,3,7). Consequently, this alteration of signaling facilitates the overgrowth of bone in FOP.
Symptoms
With the exception of monophalangism and other digital malformations present in most FOP patients at birth, babies with FOP do not exhibit telltale heterotopic ossifications (3). Usually, symptoms of bone growth start to manifest themselves within the first decade of life (5). Disease onset can be spontaneous or triggered by soft tissue damage. Swelling, pain and flare-ups of bone growth can be initiated by surgery, immunizations, soft tissue trauma, viral infections, dental procedures or even a bump (2, 3, 4, 6). Areas of the body that tend to manifest the ossifications first are the dorsal, axial, cranial and proximal areas of the body while subsequently, the ventral, appendicular, caudal and distal areas tend to transform later (1). Once an area undergoes the metamorphosis into bone, it is irreversible and permanently constrains mobility in these areas. Luckily, smooth muscle and cardiac muscle are exempt from being affected by this disease. Additionally, the tongue and diaphragm are not commonly affected either (2,6). Given the nature of which flare-ups occur, there is no surgical procedure to remove of newly developed bone. Surgery and tissue damage provoke further ossification therefore no surgical removal of bone can be done (2). An excerpt of one of the first documented accounts of FOP can be read below. This observation was written by surgeon John Freke in 1740:
"April 14, 1736. There came a boy of healthy look and 14 years of age, to ask of us at The Hospital, what should be done to
cure him of many large swellings on his back which began about three years since, and have continued to grow as large on
many parts as a penny-loaf, particularly on the left side. They arise from all the vertebre of the neck, and reach down to the
sacrum. They likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of coral do, they make, as it were, a fixed bony pair of bodice (1)."
By virtue of the rarity of FOP, the bony formations present on the spine and back are often misdiagnosed as juvenile fibromatosis (extra-abdominal desmoid tumors), fibrosacroma, chondrosarcoma, osteosarcoma, cephalohematoma or lymphedema (2). Misdiagnoses of FOP can result in unnecessary biopsies that further perpetuate the bone growth and worsen the condition (2). There is no known treatment or preventative measure for FOP at this time. The average life span of a patient with FOP is 45 years of age, however, it is recorded that some patients with FOP can live into their seventies (2). Despite this, researchers are trying to find mechanisms to understand and eventually control this puzzling affliction.
Inheritance
FOP is considered an autosomal dominant disease, meaning that in order for a person to have FOP, only one defective copy of the gene is necessary for a person to develop the disease. Complete penetrance and variable expressivity are features of the FOP phenotype. The disease gene, ACVR1, is located on chromosome two, which is an autosome. Everyone has two copies of a given gene, one of which comes from the mother and one of which comes from the father. If a parent has FOP and is heterozygous, that means that one of the two copies of chromosome two carry the mutation. If this individual were considering having a child, there is a 50/50 chance that the mutated chromosome will segregate into the gamete, consequently causing the child to inherit the disease. With this said, although an adult with FOP is occasionally capable of having children depending on the severity of the disease, many opt out of having children due to increased health risks for the FOP mother and child (5). Some of the potential risks for the mother include the risk of additional flare-ups and difficulty breathing in the later stages of pregnancy. It is necessary for the FOP mother to undergo a caesarian section due to pelvic bone deformities, bone fusion and the possibility that the birth canal may not permit a normal vaginal birth (5). However, the majority of the FOP cases actually arise from a de novo mutation in the gamete as opposed to inheriting it from an FOP parent, showing that the distribution of this disease does not discriminate against race, gender, ethnicity or geographical location since most cases of the disease arise by chance (5).
Treatment
At the present time, there is no cure for FOP. Only treatments to relieve the pain and discomfort of bone growth are available for FOP patients. Researchers hope to eradicate the disease progression by exploring various avenues for potential treatment. Modern techniques that researchers integrate into potential treatments include kinase inhibitors to block the aberrant receptor activity, RNA interference methods, the use of various drugs and attempting to divert the mesenchymal stem cell from adopting a bone cell fate (8, 9, 10, 11, 12). Moreover, future research to improve the depth and understanding of FOP mechanisms could assist in pursuing an effective treatment for FOP and other bone disorders.
FOP is considered an autosomal dominant disease, meaning that in order for a person to have FOP, only one defective copy of the gene is necessary for a person to develop the disease. Complete penetrance and variable expressivity are features of the FOP phenotype. The disease gene, ACVR1, is located on chromosome two, which is an autosome. Everyone has two copies of a given gene, one of which comes from the mother and one of which comes from the father. If a parent has FOP and is heterozygous, that means that one of the two copies of chromosome two carry the mutation. If this individual were considering having a child, there is a 50/50 chance that the mutated chromosome will segregate into the gamete, consequently causing the child to inherit the disease. With this said, although an adult with FOP is occasionally capable of having children depending on the severity of the disease, many opt out of having children due to increased health risks for the FOP mother and child (5). Some of the potential risks for the mother include the risk of additional flare-ups and difficulty breathing in the later stages of pregnancy. It is necessary for the FOP mother to undergo a caesarian section due to pelvic bone deformities, bone fusion and the possibility that the birth canal may not permit a normal vaginal birth (5). However, the majority of the FOP cases actually arise from a de novo mutation in the gamete as opposed to inheriting it from an FOP parent, showing that the distribution of this disease does not discriminate against race, gender, ethnicity or geographical location since most cases of the disease arise by chance (5).
Treatment
At the present time, there is no cure for FOP. Only treatments to relieve the pain and discomfort of bone growth are available for FOP patients. Researchers hope to eradicate the disease progression by exploring various avenues for potential treatment. Modern techniques that researchers integrate into potential treatments include kinase inhibitors to block the aberrant receptor activity, RNA interference methods, the use of various drugs and attempting to divert the mesenchymal stem cell from adopting a bone cell fate (8, 9, 10, 11, 12). Moreover, future research to improve the depth and understanding of FOP mechanisms could assist in pursuing an effective treatment for FOP and other bone disorders.
Works Cited:
1. 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
2. Clinical Reviews in Bone and Mineral Metabolism, vol. 3. Humana Press Inc. 2005. file:///C:/Users/User/Downloads/Clinical%20Reviews%20in%20Bone%20and%20Mineral%20Metabolism.pdf
3. Kaplan, F. S., Xu, M., Seemann, P., Connor, J. M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., GillessenKaesbach, G., Hoover-Fong, J., Koster, B., Pauli, R. M., Reardon, W., Zaidi, S. A., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., and Shore, E. M. (2009) Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1, Hum. Mutat. 30, 379–390. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921861/
4. 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.. 7. "Fibrodysplasia Ossificans Progressiva." Genetics Home Reference. U.S. National Library of Medicine, 9 Feb. 2015. Web. 11 Feb. 2015. http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/jbmr.1637/pdf
5. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011;6:80. http://www.ojrd.com/content/pdf/1750-1172-6-80.pdf
6. "FOP Fact Sheet." FOP Fact Sheet. International Fibrodysplasia Ossificans Progressiva Association, 2009. Web. 12 Feb. 2015. <http://www.ifopa.org/fop-fact-sheet.html>.
7. "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
8. Lowery, J.W. and Rosen, V. (2012). Allele-specific RNA interference in FOP silencing the FOP gene. Gene. Ther.19, 701–702. file:///C:/Users/User/Documents/Senior/Research%20Project/Lowery.pdf
9. Yu, P.B., Deng, D.Y., Lai, C.S., Hong, C.C., Cuny, G.D., Bouxsein, M.L., Hong, D.W., McManus, P.M., Katagiri, T., Sachidanandan, C., Kamiya, N., Fukuda, T., Mishina, Y., Peterson, R.T., and Bloch, K.D. (2008) BMP type I receptor inhibition reduces heterotopic ossification. Nat. Med. 14, 13631369. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846458/
10. https://global-factiva-com.ezproxy.library.wisc.edu/ha/default.aspx#./!?&_suid=142420524451108300144928507507
11. Dinther et al. (2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research: 091211115834058–35. http://onlinelibrary.wiley.com/doi/10.1359/jbmr.091110/abstract
12. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502040/
1. 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
2. Clinical Reviews in Bone and Mineral Metabolism, vol. 3. Humana Press Inc. 2005. file:///C:/Users/User/Downloads/Clinical%20Reviews%20in%20Bone%20and%20Mineral%20Metabolism.pdf
3. Kaplan, F. S., Xu, M., Seemann, P., Connor, J. M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., GillessenKaesbach, G., Hoover-Fong, J., Koster, B., Pauli, R. M., Reardon, W., Zaidi, S. A., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., and Shore, E. M. (2009) Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1, Hum. Mutat. 30, 379–390. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921861/
4. 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.. 7. "Fibrodysplasia Ossificans Progressiva." Genetics Home Reference. U.S. National Library of Medicine, 9 Feb. 2015. Web. 11 Feb. 2015. http://onlinelibrary.wiley.com.ezproxy.library.wisc.edu/doi/10.1002/jbmr.1637/pdf
5. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011;6:80. http://www.ojrd.com/content/pdf/1750-1172-6-80.pdf
6. "FOP Fact Sheet." FOP Fact Sheet. International Fibrodysplasia Ossificans Progressiva Association, 2009. Web. 12 Feb. 2015. <http://www.ifopa.org/fop-fact-sheet.html>.
7. "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
8. Lowery, J.W. and Rosen, V. (2012). Allele-specific RNA interference in FOP silencing the FOP gene. Gene. Ther.19, 701–702. file:///C:/Users/User/Documents/Senior/Research%20Project/Lowery.pdf
9. Yu, P.B., Deng, D.Y., Lai, C.S., Hong, C.C., Cuny, G.D., Bouxsein, M.L., Hong, D.W., McManus, P.M., Katagiri, T., Sachidanandan, C., Kamiya, N., Fukuda, T., Mishina, Y., Peterson, R.T., and Bloch, K.D. (2008) BMP type I receptor inhibition reduces heterotopic ossification. Nat. Med. 14, 13631369. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846458/
10. https://global-factiva-com.ezproxy.library.wisc.edu/ha/default.aspx#./!?&_suid=142420524451108300144928507507
11. Dinther et al. (2010). "ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation". Journal of Bone and Mineral Research: 091211115834058–35. http://onlinelibrary.wiley.com/doi/10.1359/jbmr.091110/abstract
12. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502040/
Image Sources
Figure 1: http://www.ijoonline.com/viewimage.asp?img=IndianJOrthop_2011_45_3_280_80050_f5.jpg
Figure 2: A.B. Shafritz et al., New Eng. J. Med., 335 (8): 555-61, 1996, Massachusetts Medical Society. Skeleton part of collections at the Mütter Museum, College of Physicians of Philadelphia
http://imgarcade.com/1/fop/
Figure 3: http://en.wikipedia.org/wiki/ACVR1#mediaviewer/File:Protein_ACVR1_PDB_3H9R.png
Figure 4: http://www2.le.ac.uk/departments/genetics/vgec/schoolscolleges/topics/inheritancepatterns
Video: https://www.youtube.com/watch?v=GksggHYAA7M
Figure 1: http://www.ijoonline.com/viewimage.asp?img=IndianJOrthop_2011_45_3_280_80050_f5.jpg
Figure 2: A.B. Shafritz et al., New Eng. J. Med., 335 (8): 555-61, 1996, Massachusetts Medical Society. Skeleton part of collections at the Mütter Museum, College of Physicians of Philadelphia
http://imgarcade.com/1/fop/
Figure 3: http://en.wikipedia.org/wiki/ACVR1#mediaviewer/File:Protein_ACVR1_PDB_3H9R.png
Figure 4: http://www2.le.ac.uk/departments/genetics/vgec/schoolscolleges/topics/inheritancepatterns
Video: https://www.youtube.com/watch?v=GksggHYAA7M
Cassie Heilingoetter Email: [email protected] Last Updated: May 17th, 2015 www.genetics564.weebly.com