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GENETICS Gene Found for Rare Bone Disorder May Build Understanding of Osteoporosis, Other Bone Diseases Researchers from the HSDM and Forsyth Institute joint Department of Oral Biology have discovered a genetic mutation responsible for cherubism, a childhood bone disorder. In its mild forms, cherubism causes children to develop chubby cheeks and upward-looking eyes like those of a cherub. Ernst Reichenberger (above), Bjorn Olsen, Yasuyoshi Ueki, and colleagues found a rare bone disorder gene that may contribute to understanding and treating more common bone diseases. Photo by Graham Ramsay The discovery, reported in the June Nature Genetics, may lead to potential therapies or prenatal diagnosis for the disorder, said Bjorn Olsen, chair of the HSDM–Forsyth department. The findings also provide clues to the mechanisms underlying such bone-degrading disorders as osteoporosis, according to Ernst Reichenberger, an HSDM instructor in the department. He and Olsen led the research team, which included HSDM research fellow Yasuyoshi Ueki, first author on the paper. Shifting Bone The mutation affects primarily young children starting at age 3 or 4, when secondary teeth develop inside the jawbones. "At that time, there is much bone degradation and remodeling going on," Reichenberger said. But in cherubism, "there must be something wrong with the way certain bone cells receive information from other cells or extracellular matrix." In its severe forms, cherubism can lead to excessive degradation of the jawbone. The bone tissue is replaced by soft tissue masses that cause swelling of the face and can intrude into the eye socket and force the eyeballs to tilt upwards. Cherubistic patients also suffer from chronic inflammation of lymph nodes and tooth malformation and loss. Many have difficulty chewing because of reduced jaw movement. Symptoms usually recede after puberty, and children with mild forms of cherubism generally appear normal as adults. Because no epidemiologic studies have yet been conducted, it is not known how many people have the disorder in addition to the approximately 200 reported in the medical literature. The mutation leading to cherubism appears to affect a signaling mechanism that causes both bone-degrading osteoclasts and bone-building osteoblasts to function abnormally, Reichenberger said. The discovery is complementary to that reported by department researchers in April (see The American Journal of Human Genetics, June 2001). The previous paper identified a mutation causing craniometaphyseal dysplasia, or CMD, which can lead to excessive growth of craniofacial bone. Both discoveries are important to the understanding of bone growth and degradation. The mutant gene for CMD appears to affect a protein that regulates the transport of inorganic phosphate to bones. Multitasking Mutant Because cherubism involves both bone degradation and the growth of tumorlike tissue, the researchers hypothesize that the protein, dubbed SH3BP2, functions differently in different cells in its mutant form. For example, the mutant protein may activate osteoclasts. In areas where the bone has been degraded, it may also activate osteoblasts or osteoblast precursors. These atypical osteoblasts may proliferate, fill in the cavities where bone has been degraded, and continue to grow as a fibrous tissue mass, causing the distorted facial expression of cherubistic children. Discovery of the mutant gene for cherubism is a significant step in understanding the signaling process in bone cells and could yield important clues about the development of secondary teeth, Olsen said. By comparing the faulty signaling exhibited in cherubism with normal signaling, it may be possible to pinpoint crucial mechanisms for bone remodeling. This knowledge, the researchers hope, will contribute to methods for treating or averting cherubism and could one day allow prenatal diagnosis. Even more important, however, is that understanding the signaling mechanisms exhibited in cherubism could lead to deeper knowledge and treatment of bone diseases that affect large segments of the world's population. Among these are osteoporosis and its converse, osteopetrosis. —Anita Harris