Nearly 40 percent of babies with a condition known as Simpson Golabi Behmel syndrome will die soon after birth, likely because of heart problems related to the disorder, which causes them to grow too quickly. If they do survive, additional challenges await, including skeletal defects, kidney problems, and increased risk of several types of cancers.
Researchers funded by the Children’s Discovery Institute are pursuing a unique new approach to treating this disorder: they’re hoping to use long chains of sugar molecules to coax troublemaking cells back to good behavior.
“Although a number of the birth defects in these patients are perhaps already irreversibly established at the time of birth, our research will potentially lead to treatments for the abnormal cell growth that leads to bone overgrowth and the cancer seen in these patients during childhood,” says pediatrician Scott Saunders, M.D., Ph.D., a molecular biologist who treats children with Simpson Golabi Behmel syndrome.
The hope for new treatment centers on a relatively recent insight into how cells take on specialized jobs. Although every cell in a person’s body has the same DNA, to become a red blood cell, a brain cell or a bone cell, each cell must use certain instructions encoded in DNA while ignoring others.
But scientists have recognized that these instructions aren’t just encoded in DNA and in proteins made from the DNA. They’re also encoded in sugar chains attached to certain proteins in cells. These sugar/protein hybrids are known as glycoproteins, and the unique “flavors” of glycoproteins found in different types of cells help them do their jobs.
“The protein is the same, but the sugars bound to it are different,” explains principal investigator Lijuan Zhang, Ph.D., assistant professor of pathology and immunology at Washington University School of Medicine. “This can change the function of the protein dramatically—for example, the job it does, how often it does that job, or the identity of its bosses or coworkers.”
Zhang works to understand how these properties are encoded in sugar chains. For her CDI-funded research, she will team up with Saunders and another Washington University molecular biologist, David Ornitz, M.D., Ph.D.
Glycoproteins are also topics of interest for Saunders and Ornitz, professor and head of molecular biology and pharmacology. Ornitz led the research team that discovered a family of glycoproteins that activates a growth factor receptor and helps to regulate cell growth in many different parts of the body. In developing bone, the receptor acts like a brake on cell growth and division – when it’s activated, cells are less likely to multiply.
Saunders was the first to clone a glycoprotein that activates this receptor. This was an important step to understanding how the glycoprotein and the receptor work together to control cell growth.
Mutations in this glycoprotein are the most frequent cause of Simpson Golabi Behmel syndrome. According to researchers’ theory, the mutated glycoprotein is less capable of activating the receptor, which allows bone growth to slip out of control.
Using the insights they develop into this glycoprotein signaling system, scientists eventually hope to create artificial sugar chains that can restore the function of the glycoprotein damaged by the Simpson Golabi Behmel syndrome mutation, normalizing bone growth and easing other problems. If they can, the approach may be adaptable for other genetic disorders that affect the skeleton, such as dwarfism. Skeletal birth defects are a common problem, with some international estimates placing the prevalence of these conditions at about one in every 5,000 births.
“There also may be an even wider range of applications for this new technique,” Saunders says. “Glycoproteins are involved in processes ranging from infection to inflammation, and from Alzheimer’s disease to cancer. We may want to modify some of these glycoproteins, including the ones that many parasites and viruses take advantage of to force their way into human cells.”
With CDI grant funds, the researchers plan to hire a postdoctoral fellow who will work in all three labs as they attempt to better understand growth factors, their receptors and glycoproteins.
“We all bring different pieces of the puzzle that one day may be assembled and used to treat patients,” Ornitz says.
“It’s an ideal collaboration – the whole is greater than the sum of its parts,” Saunders adds.