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Genes defective in rare disease help form bones

by Kate Ramsayer

Gerard Karsenty, MD, PhD

The short stature and brittle bones that worsen over time in patients with Coffin-Lowry Syndrome are the result of a defective protein that the production of new bone tissue, according to researchers Baylor College of Medicine in Houston.

In a paper published in the April 30 issue of Cell, scientists follow the path of missteps in this rare disease, from the gene that is mutated in people, to an intermediate protein that should be activated, to the failure of the bone-forming cells called osteoblasts to do their job.

“The disease we were looking at, Coffin-Lowry Syndrome, was known to be due to a mutation in the kinase called RSK2,” said Gerard Karsenty, MD, PhD, a BCM professor in the department of molecular and human genetics. A kinase is a protein that adds a phosphate group to another protein, often switching it to an active form. “What was not known was how the kinase was causing either the mental retardation or the skeletal abnormalities of the patients.”

Karsenty and his colleagues discovered that one of the proteins activated by RSK2 is called ATF4. They conducted a series of experiments in cell cultures and in mice to examine the effect of RSK2 and ATF4 on bone formation. Like patients with Coffin-Lowry Syndrome, mice lacking RSK2 had shorter, less dense bones and bigger gaps between the skull fragments at birth.

Mice lacking ATF4 had similar but more severe deformities. Many die at birth; possibly because their bones are so brittle that they are crushed. Within their bones, these mice have thinner, shorter, fewer of the bone tissue strands called trabeculae.

When they conducted experiments in the bone-forming osteoblast cells to determine why this happened, Karsenty and his colleagues found that cells lacking ATF4 are slower to differentiate and become mature osteoblasts. In addition, these could not produce sufficient Type I collagen, which is the main component of bone.

“This explains why the symptoms of the disease worsen over time,” said Karsenty. “The patient progressively makes less and less collagen, and the bone degenerates more and more.”

Scientists knew that ATF4 normally transports amino acids, the building blocks of proteins, into the cell. If osteoblasts don’t produce collagen in Coffin-Lowry patients because ATF4 is not importing amino acids, this could lend itself to a simple clinical treatment, said Karsenty.

“By giving patients a diet rich in protein, one could try to see if it corrects or rescues the skeletal manifestations,” he said. His lab is currently trying this in mice, while his European colleagues are conducting clinical trials in people.

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