January 9, 2002
MEDIA CONTACT: David Bricker
PHONE: 410-223-1728
E-MAIL: dbricker@jhmi.edu

Basis of Rare Genetic Illness Leads To Better Understanding of Bone Formation, Hopkins Researchers Find

Scientists at Johns Hopkins and three other centers have found that defects in GNAS1, a hormone sensitivity gene, are responsible for progressive osseus heteroplasia (POH), a disease that causes rice-size bone fragments to spontaneously form under the skin and inside internal organs. The finding, reported in this week's New England Journal of Medicine, also represents a major step forward in identifying the genes responsible for normal bone formation in children and adults, a process that has largely mystified scientists.

"This new knowledge will allow us to design medical treatments that block problem-causing bone fragments in patients," says Johns Hopkins Children's Center endocrinologist Michael Levine, M.D., a principal investigator of the research project. "But the real excitement, I think, comes from understanding POH as a model for new bone formation. This in turn may help us discover new agents that induce new bone growth and that may be useful treatments for many other bone problems, including osteoporosis and bone fractures."

The research may also prove important to core geneticists because of the role "genomic imprinting" plays in the expression of the defective GNAS1 gene. When a gene is imprinted, only one gene in the pair will be active in
each cell. As yet, few concrete examples of genetic imprinting exist for researchers to study.

GNAS1 (guanine nucleotide binding protein alpha stimulating activity polypeptide) provides the DNA blueprint for Gs-alpha, a protein that plays a critical role in a cell's ability to respond to its external environment. Part of an elegantly complex metabolic system called a signal transduction pathway, Gs-alpha at normal levels allows cells to respond to hormones by influencing which genes are turned on and off, as well as controlling the action of many proteins. Adefect in GNAS1 prevents cells from responding to hormones. In POH's case, this leads to the synthesis of bone by affected
cells.

The research team examined 18 unrelated individuals diagnosed with POH. All study participants had relatives who had also been diagnosed with POH. Sequenced DNA showed that of the 18 study participants, 13 possessed one
mutant copy of the GNAS1 gene. The prevalence of the GNAS1 mutation was high enough to implicate the gene as a major cause of POH, though other factors may contribute, researchers concluded.

Patients diagnosed with POH develop spontaneous bone fragments under the skin and deep inside their bodies throughout life. The lesions caused by POH can be identified, leading to diagnosis soon after birth. Levine
estimates one of every 100,000 individuals is affected by the disorder.

Researchers from the Johns Hopkins School of Medicine, the University of Pennsylvania School of Medicine, the Royal Children's Hospital in Melbourne, Australia, and the Washington University School of Medicine also
contributed to the report. It was funded by grants from the National Institutes of Health and The Johns Hopkins University School of Medicine's General Clinical Research Center.

"Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseus heteroplasia (POH)" New England J. Med. Vol 346 No. 2, pp. 99-106



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