May 16, 2002 New Haven, Conn. — By identifying a genetic mutation that causes extremely high bone density in people, Yale researchers have found a potential target for the prevention or treatment of osteoporosis, it was reported Thursday in the New England Journal of Medicine. The finding was made when the senior investigators, Richard Lifton, M.D., chair of the Department of Genetics at Yale School of Medicine, and Karl Insogna, M.D., professor of internal medicine and director of the Yale Bone Center, identified a Connecticut family with bones so strong they rival a character in the recent movie, "Unbreakable." Osteoporosis is a loss of bony tissue that leads to fragile bones.
"If there are living counterparts to the character in ‘Unbreakable,’ who is in a terrible train wreck and walks away without a single broken bone, it’s members of this family," Lifton said. "They have extraordinarily dense bones and there is no history of fractures. You find this maybe once in a million people."
Lifton said those family members with the genetic mutation have no symptoms. They do have a strikingly deep and wide jaw and bony growth on the palate. They also report trouble staying afloat when swimming.
Twenty members of the extended family helped in the genetic hunt by providing blood samples for DNA testing and most had their bone density measured.
Seven of the family members tested had extremely high bone density in the spine, the hip, and throughout their bodies, while nine of the family members had entirely normal bone density. Detailed serum and urinary biochemical measurements were performed in four of the participants with very high bone density. These were then compared with results from nine healthy control subjects.
"What we found is that the high bone density in this family behaved as a single gene disorder," Lifton said. "We then went on to map the location of the gene and identified the specific mutation responsible for the high bone density."
Insogna told Lifton about the family following a discussion with another co-author, Joseph Belsky, M.D., clinical professor of internal medicine.
"Dr. Belsky mentioned a few years ago, in the context of a clinical case being studied at Yale, that he was aware of a family that had high bone density," Insogna said. "I mentioned that I too had been referred a patient with extraordinarily high bone density. When we pieced together the family tree, we realized these people were all related."
Insogna said the significance of the finding is that it identifies a pathway, the so-called Wnt signaling pathway, in bone cells that appears to be very important for controlling bone mass. "The genes that control bone mass were not known, and still are largely unknown," he said. "But our findings point to a family of genes that apparently have an important role in controlling bone mass."
This finding follows a study published last year that demonstrated low bone density could be caused by a mutation that causes a loss in the function of the gene, LRP5. Lifton said he and his team mapped the gene in the family to the same chromosome segment in LRP5.
"It made us wonder if a different mutation increased LRP5 function leading to an opposite phenotype, that is, high bone density," Lifton said.
Bone mass increases during childhood and peaks at about the age of 20. It is a major determinant of the risk of osteoporotic fracture. Nearly one million fractures occur annually in people over the age of 65, the majority of which are due to osteoporosis. Twin and family studies indicate that genetic factors account for about 75 percent of the variation in peak bone mass.
"Importantly, this study also demonstrates that prevention of the normal inhibition of LRP5 by Dkk, another developmental protein, causes high bone density without other clinical side effects," Lifton said. "The biochemical changes in the blood of these individuals," Insogna added, "are consistent with the idea that the LRP5 pathway is activated in this family."
The Yale investigators feel that these findings suggest a new route by which to develop medications to increase bone density and prevent or treat osteoporosis.
Other researchers included Lynn Boyden, Anita Farhi, Lyle Mitzner, M.D., Mary Mitnick, all of Yale, and Junhao Mao and Dianqing Wu, both of the University of Connecticut Health Center in Farmington.
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