A genetic region thought to be critical to the development of Down syndrome (search) may only be part of a much more complex genetic phenomenon responsible for the disease, according to a new study done on mice.

Researchers say the findings refute the long-held notion that genes in this region are largely responsible for the characteristic facial features and other common traits of Down syndrome.

Down syndrome is the most common cause of mental retardation and affects about one in 700 births. The most common physical traits seen in children who have Down syndrome include a flat facial profile, an upward slant of the eyes, abnormally shaped ears, and an enlarged tongue.

For more than 30 years, many researchers had suspected that a particular gene on chromosone 21 (search), which is found in triplicate in people with Down syndrome, was a key player in the development of the condition. This extra genetic material changes the development of the fetus and can lead to the physical characteristics of the syndrome. As a result, the region became known as the "Down Syndrome Critical Region" (search) or DSCR.

But by using a mouse model of Down syndrome, researchers found having three copies of the DSCR genes was not sufficient to cause the facial abnormalities typical of the disorder.

"The simplistic idea that just one of the hundreds of genes on chromosome 21 affects development no longer holds up," says researcher Roger Reeves, PhD, professor of molecular biology and genetics at Johns Hopkins Institute for Basic Biomedical Sciences, in a news release. "Now researchers can take a deep breath, accept that the syndrome is complex, and move forward."

New Direction for Down Syndrome Research

In the study, which appears in the Oct. 22 issue of the journal Science, researchers created genetically engineered mice that had either three copies or one copy of the genes in the suspected Down syndrome region and analyzed them.

"These mice weren't normal, but they weren't Down syndrome mice, either," says Reeves. "Their faces were longer and narrower than normal, but Down syndrome is characterized by shorter-than-normal facial bones."

In addition, researchers found that DSCR didn't seem to be required for the development of Down syndrome-like facial features. The study showed that mice with the normal number of two copies of the genes in this region, but three copies of the genes on the rest of the chromosome did have the characteristic facial features of Down syndrome.

Researchers say the results indicate that abnormalities in the DCSR region are part of a larger, more complex process in the development of Down syndrome.

"Some genes in the region contribute to the effects on facial bones, but, in triplicate alone, this region produces different traits than those seen in Down syndrome," says Reeves. "If anyone is going to try to treat the problems seen in Down syndrome, we need to understand what is really happening and when in development it happens."

In a related article in the same journal, David Nelson and Richard Gibbs of Baylor College of Medicine say the study firmly refutes the notion that having three copies of the genes in the suspected region is the sole cause of Down syndrome.

Although the notion that only a few genes may be of critical importance in the development of Down syndrome is appealing because it would make developing potential therapies easier, they say the findings will allow researchers to further study the other 33 genes associated with Down syndrome abnormalities.

By  Jennifer Warner, Reviewed by  Brunilda Nazario, MD

SOURCES: Olson, L. Science, Oct. 22, 2004; vol 306: pp 687-690. News release, Johns Hopkins M