X-Message-Number: 27244
Date: 19 Oct 2005 13:55:54 -0700
From: 
Subject: [News] NanoAging.com News

Rett Gene Regulates Alternative Splicing



The gene responsible for Rett syndrome, a devastating neurological disease found
mostly in girls, 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, said Baylor College of Medicine researchers in a report 
appearing online today in the Proceedings of the National Academy of Sciences.


The finding brings a new understanding to the ongoing process of unraveling the 
mystery behind why neurons work and do not work.<br />
<br />

"There are multiple steps that a neuron goes through as it makes a decision to 
communicate with another neuron," said senior author Dr. Huda Y. Zoghbi, 
professor of pediatrics and human and molecular genetics at BCM 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.<br />
<br />

"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.<br />
<br />

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.<br />
<br />

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. <br />
<br />

Genes are organized into portions that code for proteins (called exons) and 
intervening sequences (called introns). Normally a cell pastes together the 
exons to generate the RNA that will be translated to a protein. In alternative 
splicing, the cell uses various combinations of exons to generate diverse sets 
of RNA and proteins. That is the reason that fewer than 30,000 human genes are 
predicted to make more than 100,000 proteins.<br />
<br />

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 than the expected gene expression changes given the known role of 
MeCP2 in regulating gene expression.<br />
<br />

"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." <br />
<br />
<br />
###<br />

Others who participated in this research include: Juan I. Young, Eugene P. Hong,
John Castle, Aaron B. Bowman, Matthew F. Rose, Dongcheul Kang, Ron Richman and 
Susan Berget, all of BCM, and Juan Crespo-Barreto and Jason Johnson of Rosetta 
Inpharmatics, LLC, Merck & Co. Funding for this work came form the Howard Hughes
Medical Institute, Rett Syndrome Research Foundation, the National Institutes 
of Health, the Hereditary Disease Foundation and Cure Autism Now.<br />


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