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.
This finding may explain the symptoms associated with this puzzling disorder and others related to it, said Baylor College of Medicine scientists 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.
"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 a number of 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.
Researchers 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 a number of different proteins.
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.
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.".
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 and 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.