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Mutated Protein for Rett Syndrome Silences and Activates Gene Expression


doi: 10.1097/01.NT.0000326359.34176.72
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Investigators report that mutations in the gene that cause Rett syndrome both silence and activate gene expression.

Genetic diseases are rarely straightforward, as the team of scientists who in 1999 first identified the gene for Rett syndrome, one of the few disorders inherited as an X-linked dominant condition, has discovered.

In a new study in the May 30 Science, they describe the X-linked gene for the methyl CpG-binding protein2 (MeCP2); mutations in this gene cause the disorder, which affects one in 15,000 girls. They have found that the mutations do more than silence gene expression — repressing transcription (the process by which a gene's DNA is read to produce messenger RNA) and causing the protein to lose its function. It also activates transcription, inducing changes in the expression levels of thousands of genes, according to lead study author Huda Y. Zoghbi, MD, professor of pediatrics, molecular and human genetics, and neuroscience at Baylor College of Medicine in Houston, TX, and an investigator with the Howard Hughes Medical Institute.

A single gene mutation was enough to disrupt the normal functioning of more than 2,500 genes. Gene expression went up and down— and it was the exact opposite genetic disruption in those with too much protein. The investigators were surprised to see so many gene expression changes and that the mutation was both suppressing and activating gene expression.

The latest finding may help in understanding the complex nature of many other genetic conditions. “Thousands of genes are changed by MeCP2,” said Maria Chahrour, a graduate student in Dr. Zoghbi's lab and first author of the report. This study shows that symptoms, while similar, can have different genetic causes and thus require different treatments.

Dr. Zoghbi and other investigators have been searching for differences in gene expression that could explain the vast range of symptoms in patients with Rett syndrome, which affects both boys and girls, but is predominantly fatal in boys. (See “Gender, Rett Syndromes.”) For years, they seemed to come up empty-handed at every turn.

“If something represses transcription, its loss will cause the activation of many other genes,” explained Dr. Zoghbi. “But we couldn't identify targets of this protein [MeCP2].”

The investigators decided to narrow the search for gene expression to the hypothalamus, because it seems to be associated with Rett disorder symptoms, including anxiety, an abnormal response to stress, gut motility issues, sleep problems, and cold hands and feet.

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In the current study, the investigators did a microarray analysis of DNA expression in hypothalamic tissue from two mouse models — a gene knockout with no expression of the MeCP2 protein and a transgenic mouse that increases the number of copies of the gene. They compared the differences in gene expression in each of the models and then looked at expression in an animal with a normal gene.

In the Rett syndrome mouse model, about 85 percent of the genes were relatively silenced from doing their job; the exact opposite ratio of activation was found in those with a doubling dose of the protein. They also found that it activates CREB1 (CAMP responsive element binding protein), a gene that increases or decreases the transcription of certain other genes. CREB proteins are active in many species, from the lowly fruit fly to humans.

“These two mouse models display molecularly opposite changes, yet they share many phenotypes,” explained Dr. Zoghbi, “Proteins don't work in isolation. They have partners. And if you have a dominant partner it disrupts the balance, whether you have too much of something or too little. The final symptoms are a sign of unhappy neurons.”

The findings also pose problems for the design of a genetic strategy for this disease. With so many transcriptional changes in the hypothalamus — they are now looking at other regions as well — they will have to identify another strategy to stop this genetic process to prevent the devastating symptoms that stop normal development in its tracks. And given that having exactly the right level of MeCP2 is critical for neurons to be healthy, “the idea of gene therapy gets much harder” to consider, said Dr. Zoghbi. “The dosage is critical.” Since thousands of genes are involved and some are turned on and others are silenced, “we have to figure out a way to get these genes regulated correctly,” she added.

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“It is an important finding,” said Ljubisa Vitkovic, PhD, program director of the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers, funded by the NIH National Institute of Child Health and Human Development. The government provides funds to 14 programs around the country for research on developmental disabilities. Dr. Zoghbi is one of these grant recipients.

“It was thought that if we could make up for what is missing by adding protein we could prevent this syndrome from developing,” said Dr. Vitkovic. “But it is much more complex than we realized.” He said that the old paradigm — one gene, one protein, one phenotype — is just not true. Instead, “We need to think about gene and protein networks. We need to broaden our perspective and identify large networks of genes that are altered by this mutation.”

Dr. Zoghbi said that mutations in the MeCP2 gene might also explain some cases of autism, learning disabilities, and mental retardation that have defied other medical explanations. “This mutation may affect one in every 5,000 people, or more. We just don't know,” Dr. Zoghbi said.

Scientists have shown that the expression of genes can be manipulated by adding methyl groups. One common methyl donor is folic acid, and Dr. Zoghbi's team has an ongoing clinical trial to test whether folic acid supplements can prevent Rett syndrome or rescue some of the functional loss in older children. Clinical trials are now under way.

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Rett syndrome affects both sexes but it seems to be fatal early on in boys because they don't have a normal copy of the MeCP2 gene. Rett is an X-linked dominant disorder, which means that if a mutated copy of the gene is passed down to sons, they do not have a normal copy. They receive one X-chromosome and one Y-chromosome.

But girls receive two X-chromosomes, so that they can have a normal copy of the gene and a mutated one. The condition still causes a laundry list of complex symptoms because every cell in the body is producing half of the needed protein when there is a mutated form of the gene. The expression of some level of the protein is enough to spare girls from death but not enough to save them from the disease and its symptoms. Children with Rett syndrome learn to walk, talk, and interact socially, but between six to 18 months they lose the developmental milestones. They never recover. Many become wheelchair-bound or walk with an abnormal, stiff gait. They also suffer breathing problems and tremors.

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• SEATTLE, WA • April 25-May 2, 2009

• TORONTO, ON • April 10-April 17, 2010

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•Chahrour M, Jung SY, Zoghbi HY, et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 2008;320:1224–1229.
    ©2008 American Academy of Neurology