The gene responsible for Rett syndrome not only silences some genes but in combination with another also regulates alternative splicing, crucial to the formation of proteins -- a finding that may explain the symptoms associated with this puzzling disorder and others related to it.

" There are multiple steps that a neuron goes through as it makes a decision to communicate with another neuron," said senior author Huda Y. Zoghbi, at Baylor College of Medicine as well as a Howard Hughes Medical Institute investigator. " The neuron will express certain genes producing RNA, make certain proteins from these RNAs, and then carry some of these proteins to synapse. Alternative RNA splicing is one way for the cell to create many different forms of RNA and proteins from the same gene. We are just beginning to learn the importance of alternative splicing in neuronal activity." Zoghbi discovered the role of the gene methyl-CpG binding protein 2 ( MeCP2 ) in Rett.

" In fact, the effect of this protein ( MeCP2 ) on RNA splicing is more noticeable than its effect on gene expression," she said.

Rett syndrome occurs in approximately 1 in 10,000 girls.
As infants, those who have the disorder seem normal at birth and at least six months after.
Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk.
Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior.
Often they develop a curvature of the spine, difficulty in interacting with other people and mood disorders, among other problems.
At some point, the regression stops but they do not acquire new abilities.

Scientists know that mutations in MECP2 are associated with these symptoms in Rett as well as other disorders such as autism and a variety of X-linked mental retardation syndromes as well.

Understanding how one gene could result in all these problems led Zoghbi and her team to take a new look at MeCP2, which was known to repress the expression of some genes.
In studies involving cells and mice, they found that a protein called Y box-binding protein 1 or YB-1 binds to MeCP2 consistently.
YB-1 protein is involved in regulation of alternative splicing, a process by which one gene can provide the code for many different proteins.

Loss of MeCp2 function can cause dramatic changes in alternative splicing, said Zoghbi. In fact, these changes are more evident in a mouse model of Rett syndrome than the expected gene expression changes given the known role of MeCP2 in regulating gene expression.

" When a gene level is increased or decreased by 20 to 40 percent, as has been found for some of the gene targets of this protein, you expect consequences," she said. " When the gene makes a different protein, however, you can expect more severe consequences in the neuron."

Source: Baylor College of Medicine, 2005


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