Researchers at the Howard Hughes Medical Institute at Baylor College of Medicine in Houston and Stanford University have discovered the defective gene responsible for Rett syndrome, a degenerative neurological disease of infant girls. The finding has implications for both the development of a test to diagnose the disorder before birth, as well as new strategies to prevent the debilitating effects of the disease. A paper describing the identification of the Rett's Syndrome gene was published in the October issue of Nature Genetics.
"Rett syndrome affects roughly 1 in every 10,000 females," says Huda Zoghbi, the study's senior author, from Baylor. "At about 6 to 18 months of age, otherwise normal children gradually stop responding to and interacting with their parents."
Eventually, Rett syndrome girls lose the ability to speak, walk, and purposefully use their hands. The children may develop repetitive hand motions, such as hand wringing or hand "washing." They may also develop breathing abnormalities and experience sudden, unexpected heart attacks.
The genetic abnormality responsible for Rett syndrome was identified in a region of the X chromosome. The researchers found that the disorder results from the mutation of the gene that makes methyl cytosine binding protein 2 (MECP2).
"This was an absolute surprise, the last gene I would have ever expected to be involved in Rett syndrome," says Uta Francke, head of the Stanford group who collaborated with Zoghbi. "The fact that knocking out the gene in mice led to developmental arrest and death of the fetus seemed to rule it out as a candidate."
MECP2 is an important element in an elaborate network of proteins needed to switch off a group of genes. In the absence of this genetic switch, certain genes fail to shut down, and excessive amounts of otherwise beneficial proteins are made.
The cells that have an active X chromosome with a normal MECP2 gene confer some protection against excessive amounts of the proteins, and so infants with Rett syndrome do not develop any ill effects for a time. The molecular events leading to their decline in the second year of life can be explained by the over expression of certain genes that govern the development of the nervous system.
Males with the mutant version of the MECP2 gene on their single X chromosome die before birth.
The National Institute of Child Health and Human Development (NICHD), which funded Zoghbi's research, will immediately seek grant applications for studies that manipulate the MECP2 gene to slow, reverse or prevent the progression of Rett Syndrome. A more immediate result will likely be a test for the early diagnosis and prenatal detection of the syndrome in the rare families where the mutation is inherited.
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