“Unbreakable” bones prompt a hunt for genes

The DNA of an extended Connecticut family has yielded a possible target for the treatment and prevention of osteoporosis, according to Yale scientists who reported their findings in the May issue of The New England Journal of Medicine.

Members of this family carry a genetic mutation that causes high bone density. They have a deep and wide jaw and bony growth on the palate. Richard P. Lifton, M.D., Ph.D., chair of the Department of Genetics, along with Karl L. Insogna, M.D., professor of medicine and director of the Yale Bone Center, and colleagues, traced the mutation to a gene that was the subject of an earlier study. In that study researchers showed that low bone density could be caused by a mutation that disrupts the function of a gene called LRP5. In the recent study, the Yale team mapped the family’s genetic mutation 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.

Family members, according to the investigators, have bones so strong they rival those of a character in the 2000 movie Unbreakable. “If there are living counterparts to the [hero] in Unbreakable, who is in a terrible train wreck and walks away without a single broken bone, they’re members of this family,” said Lifton. “They have extraordinarily dense bones and there is no history of fractures. These people have about the strongest bones on the entire planet.”

Insogna first heard about the family a few years ago during a discussion of a clinical case being studied at Yale. Joseph L. Belsky, M.D., clinical professor of medicine, told Insogna that he knew of a family with high bone density. “I mentioned that I, too, had been referred a patient with extraordinarily high bone density,” Insogna said. “When we pieced together the family tree, we realized these people were all related.”

Ultimately, 20 members of the family provided blood samples for DNA testing, and most also had their bone density measured. Seven had extremely high bone density in the spine, hip and throughout their bodies. Nine family members had normal bone density.

“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 identify the specific mutation responsible for the high bone density.” The study demonstrated that the mutation prevents the action of a normal antagonist of the Wnt signaling pathway, resulting in unopposed Wnt signaling and increased bone formation.

Most importantly, the new finding suggests that medications that mimic the effect of this mutation would promote increased bone density, providing a rational target for new drug development.