Fibrodysplasia ossificans progressiva (FOP) is one of the rarest genetic diseases. But for the estimated 2,500 who have FOP, the result is nothing short of devastating. During early childhood, their bodies' muscles, tendons, ligaments and other connective tissues undergo a metamorphosis to bone, rendering them permanently unable to bend or even move. Any attempt to remove this unwanted bone leads to explosive growth of even more bone.

Scientists have known for some time that FOP is caused by a faulty gene, but finding the responsible gene became a 15-year quest for University of Pennsylvania orthopaedic surgeon Frederick Kaplan, M.D., whose work was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). In the April 23 advanced online edition of Nature Genetics, Dr. Kaplan, his colleague Eileen Shore, Ph.D., and their international collaborators reported disease-causing mutations of a gene called ACVR 1 on the long arm of human chromosome 2. The gene encodes a protein called activin receptor type 1A, a bone morphogenetic protein receptor which controls the formation of cartilage and bone.

So far, Dr. Kaplan and his colleagues have examined the ACVR1 genes in more than 60 patients with classic features of FOP. "Every one of them has the exact same DNA sequence change in the exact same spot in the gene," says Dr. Kaplan. "The FOP mutation changes one DNA letter out of six billion DNA letters in the entire human genome."

While Dr. Kaplan calls the discovery of the gene a "monumental milestone," he also says that is it just one critical step in the understanding and treatment of the disease. "My hypothesis," says Dr. Kaplan, "is that the mutation alters the sensitivity and specificity of tissue repair stem cells to trauma." Stem cells are cells in the body that have the ability to differentiate into other cell/tissue types, allowing them to replace cells that are injured or that have died. When the body is injured, he explains, damaged tissues recruit stem cells to repair the abnormality. The same thing happens in FOP, but those stem cells are expressing the mutant receptor and that mutant receptor is triggering those cells to become cartilage and bone. As a result, a bruise or bump that most people would scarcely notice is likely to cause a permanent ribbon, sheet, or plate of bone in a child with FOP.

While the quest to find the responsible gene has ended, the mission is now to find a treatment for the disease, which at this time is untreatable. The discovery of the mutation immediately suggests an approach to treatment: either to block the renegade proteins or to destroy the message coming from the mutant copy of the gene that creates the renegade proteins, says Dr. Kaplan. The discovery also offers potential applications for other problems associated with either too much bone (such as bone spurs that occur in osteoarthritis or excessive bony formation that can complicate total hip replacement, brain injury, spinal cord injury or war wounds) or too little (such as osteoporosis, limb defects, or fractures that fail to heal).

"In FOP, the bone that forms is normal, it's just in the wrong places at the wrong times for the wrong reasons," says Dr. Kaplan, whose work has also been funded by the International FOP Association (www.ifopa.org), and donations from friends and family members of FOP patients around the world. "If you could harness the genetic switch that produces bone, you could possibly make bone where you need it - such as in a bone damaged by trauma or in a bone defect after a tumor resection, or in a spinal fusion," he says. "This is the first really dramatic insight we have had into the genetic and molecular biology of forming a second skeleton."

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov. Information on osteogenesis imperfecta and other bone disorders is available from the NIH Osteoporosis and Related Bone Diseases~National Resource Center; phone toll-free 800-624-BONE (2663), or visit http://www.niams.nih.gov/bone.

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Shore EM, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics. 2006;38:525-526.