A relentless, 15-year hunt for the gene behind a rare and horrifying bone disease has ended, with a single DNA base emerging as the culprit. The newly discovered mutation not only has therapeutic implications for the currently untreatable disorder, called Fibrodysplasia Ossificans Progressiva (FOP), but it may also reveal novel avenues for producing prolific amounts of healthy bone for patients in need.
In people with FOP--2500 or so are thought to be living today with the disease--muscle and connective tissue gradually turn to bone, freezing the neck, spine, hips, and even jaw into place and trapping patients inside a "second skeleton." Orthopedic surgeon Fred Kaplan, geneticist Eileen Shore, and their colleagues at the University of Pennsylvania in Philadelphia and elsewhere knew that the simplest way to find a disease gene is through families in which more than one person is afflicted. But families with more than one FOP member are vanishingly rare--few sufferers have children, and most develop the disease because of a random mutation. So Kaplan issued an "all points bulletin" to doctors worldwide to send families his way.
In the end, just five families provided the critical DNA that led Kaplan's team to a mutation in a gene called ACVR1. ACVR1 lies along a well-known pathway that controls the formation of bone and cartilage. When activated, the gene boosts production of a so-called bone morphogenic protein that spurs bone growth; it also clamps down on other proteins that inhibit bone proliferation. In people with FOP, the ACVR1 protein is abnormal and may be overactive. The single nucleotide variation identified in the five families has been found in all 32 FOP patients tested and is absent from all of the 159 controls, the team reports online 23 April in Nature Genetics.
"That it's so specific is pretty amazing," says William Gelbart, a geneticist at Harvard. Gelbart hopes that an FOP mouse model can now be created, allowing for deeper study of the disease. Kaplan, Shore, and others are already working on artificially boosting the gene's expression in mice.
In other people, boosting ACVR1's expression locally could be a way to create bone grafts for anything from osteoporosis to trauma that leads to bone loss. "We always need hard tissue," says Patrick Warnke of the University of Kiel in Germany, who is exploring ways to grow bone and performs facial reconstruction on patients who have lost bone to cancer or trauma. The FOP gene defect, he says, could "show us the way to induce bone growth" and "enhance [it] to the maximum."
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