“Unbreakable” bones prompt a hunt for genes

Aided by a Connecticut family with unusually high bone density, a Yale team sheds light on osteoporosis.

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.

In experiment with rats, an engineered peptide helps the spinal cord regenerate

Building on their previous research, scientists at Yale have developed a synthetic peptide that promotes nerve fiber growth in the damaged spinal cords of laboratory rats.

If applied to humans, this finding could reverse the effects of brain and spinal cord injuries resulting from trauma, stroke or degenerative diseases such as multiple sclerosis. The study, published in the May 30 issue of Nature, confirms which molecules block axon regeneration in the spinal cord, according to lead author Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Chair of Neurology. It also shows that a peptide can spur new growth. Axons extend from neurons and carry nerve impulses to target cells.

In previous research Strittmatter discovered a protein he called Nogo, which inhibits regeneration of axons. A subsequent paper described the receptor through which Nogo acts. His latest research has found a way to counteract the action of the Nogo protein.

“We developed a way to block Nogo with a peptide that binds to the Nogo receptor and prevents it from doing its normal job,” said Strittmatter. “There is no drug used today to promote axon recovery in humans, so it is hard to predict how well this drug will work in humans.”

In laboratory rats the drug did promote the growth of nerve fibers, and the rats could walk better than those that did not receive the treatment. The peptide, comprising 40 amino acids, was inserted into each rat’s spinal canal through a catheter over four weeks. Human trials will not begin until researchers determine whether the synthetic peptide can promote nerve fiber growth for weeks or months after injury, and whether the peptide is effective and safe for use in humans.

“There is some reason to think the peptide might promote growth in older injuries, because some damaged nerve fibers in the brain and spinal cord just sit there,” Strittmatter said. “If we had some way to block these inhibitors the nerve fibers might grow back again.”

Et Cetera

SIDS and a faulty neuron

A study by Yale physicians suggests that sudden infant death syndrome (SIDS) may be linked to a defect in a neuron that alerts the body to high carbon dioxide levels.

“When someone falls asleep with their face in a pillow, carbon dioxide levels rise,” said George B. Richerson, M.D., Ph.D., HS ’91, associate professor of neurology and physiology. “The normal response is to wake up slightly, turn the head and breathe harder. There is evidence that some infants who die of SIDS lack this normal protective response.”

SIDS strikes one in 1,000 infants and is the leading cause of death of children between two weeks and one year of age. Physicians have identified risk factors including lying face down, prematurity, low birth weight and a recent, mild upper-respiratory infection. Previous studies had found abnormalities in serotonin-containing neurons in the brains of infants who died of SIDS. Richerson and his co-investigators reported in Nature Neuroscience that, in rats, serotonergic neurons are situated next to large arteries in the brain, an ideal location for sensing carbon dioxide levels in arterial blood.

Seeking genes and proteins

As part of a billion-dollar investment in science and engineering, the university announced in April that it will spend more than $200 million on the new Yale Center for Genomics and Proteomics, which will explore the myriad functions and interactions of genes and proteins in a range of organisms including humans. The research will help scientists understand basic biological processes and promises to open doors for the diagnosis and treatment of disease. “In addition to research, the center will be used for teaching and to amplify our interactions and partnerships with industry,” said Director Michael Snyder, Ph.D., chair of molecular, cellular and developmental biology. Added Graduate School Dean Susan Hockfield, Ph.D.: “We’ve designed a structure that provides access to state-of-the-art technology to scientists all over our campus, and that will encourage collaboration in research and teaching. … Our aim is to create a center without walls.”


			Originally published in Yale Medicine, Autumn 2002. Copyright © 2002 Yale University School of Medicine. All rights reserved.