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By Merritt McKinney
NEW YORK, Mar 13 (Reuters Health) - Scientists have moved a step closer to understanding what causes an inherited neurological disorder known as Rett syndrome.
About one out of every 10,000 to 15,000 female infants develops Rett syndrome, which is one of the leading causes of mental retardation in girls. At first, these infants develop normally, but when they are 6 months to 18 months old children with the syndrome begin to lose control of their movements and develop seizures and autism.
A mutation in the gene MECP2, which is found on the X ('female') chromosome, is known to cause Rett syndrome, but exactly how the mutation leads to the condition has been uncertain, Dr. Adrian Bird, of the University of Edinburgh in Scotland, told Reuters Health.
Bird's team, and a second set of researchers led by Dr. Rudolf Jaenisch at the Massachusetts Institute of Technology in the US have succeeded in developing a mouse version, or model, of Rett syndrome. Both teams created genetically engineered mice that lack functional versions of Mecp2, the protein encoded by the MECP2 gene. The results of both teams' experiments appear in the March issue of the journal Nature Genetics.
"Having a mouse model that recapitulates the syndrome represents a big step forward, as it give us the opportunity to find out what is actually wrong in these patients," Bird said. As is the case in humans with Rett syndrome, the mice engineered to lack Mecp2 developed stiff movements, breathing irregularities and reduced movements. These symptoms tended to develop in mice 6 to 12 months after birth, about the same time that symptoms usually start in humans.
This is surprising, according to Bird, since mice develop much more rapidly than people. It is common for female mice to have raised three litters by age 6 months, he pointed out, while human infants have not even started walking by that age.
That mice and human infants develop symptoms about the same time suggests that neurons may function normally for a while without Mecp2 "but cannot keep going for more than a few months," according to Bird.
Experiments in mice also suggest that it is the lack of Mecp2 in the brain, not in other parts of the body, that are to blame for Rett syndrome. The protein is found in cells throughout the body, but when the gene for the protein was removed from the brain, but not from other organs, symptoms developed as well.
"Our work shows that (the) absence of Mecp2 in the brain is the real cause of the problem," Bird said.
The protein may have an "ongoing and critical role" in the proper functioning of neurons, Jaenisch and colleagues note in their report. Symptoms of the syndrome may only develop once levels of the protein become depleted, according to the researchers. Assuming this theory is correct, eventually it may be possible to prevent the symptoms, they suggest.
In his comments to Reuters Health, Bird agreed, noting that it may be possible to block symptoms with drugs, although "we are some way from that stage at the present."
"We are optimistic that the mouse model will shed light on the mechanisms that give rise to Rett syndrome," Bird said. "There are exciting times ahead in Rett syndrome research."
SOURCE: Nature Genetics 2001;27:322-331.
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