Study finds two genes affect anxiety, behavior in mice with too much MeCP2

January 8, 2012

The anxiety and behavioral issues associated with excess MeCP2 protein result from overexpression of two genes (Crh [corticotropin-releasing hormone] and Oprm 1 [mu-opioid receptor MOR 1]), which may point the way to treating these problems in patients with too much of the protein, said Baylor College of Medicine scientists in a report that appears online in the journal Nature Genetics.

Much of the work was done at the Jan and Dan L. Duncan Institute at Texas Children's Hospital.

MeCP2 is a "Goldilocks" in the protein world. When the protein is lacking or defective, girls develop the Rett syndrome early in life. Too much protein results in the more recently identified MeCP2 duplication syndrome, which usually affects boys, who may inherit the gene duplications either from their mothers or, in rare cases, develop it sporadically. In both cases, anxiety and social are typical of those with the disease, along with other motor problems and cognitive defects.

"This is a nice example of a translational story," said Dr. Rodney Samaco, assistant professor of molecular and at BCM and first author of the paper. "We first identified the for MeCP2 duplication syndrome and then found people with the disorder in the clinic. We went back to the lab and found out that MeCP2 was indeed the major contributor to this phenotype in patients. We have now identified two involved in two major symptoms of the syndrome. Eventually, we may take the information back to the clinic to develop a treatment for patients."

"Loss or Gain of MeCP2 affects the expression of hundreds of genes, but discovering that two genes are the culprits in mediating anxiety and social behavioral problems is surprising," said Dr. Huda Zoghbi, professor of molecular and human genetics, neurology, neuroscience, and pediatrics at BCM and director of the NRI. She is the corresponding author of the report and a Howard Hughes Medical Institute Investigator.

Patients with MeCP2 duplication disorder have a duplication in chromosomes that span both the MECP2 gene and another called IRAK1. But with this new study, it is now clear that excess MeCP2 accounts for the neuropsychiatric symptoms.

In mice, doubled MeCP2 levels caused both anxiety and autism-like behaviors and altered the expression of several hundred genes. Of these, two genes – Crh and Oprm1, are implicated in anxiety and social behavior, said Samaco.

"Then, when we reduced the levels of Crh, we saw reduced anxiety," he said. "When we reduced levels of Oprm1, we improved the social behavior problems."

This finding is important because it shows that tweaking the expression of genes that the protein affects, rather than trying to adjust the levels of the finicky MeCP2 protein itself, can modify symptoms of MeCP2 disorders.

In fact, Samaco also reduced levels of the that is a cellular receptor for Crh, both through molecular means and with the use of a drug, and found that anxiety levels also went down. That could provide another means of dealing with associated with the duplication syndrome.

Explore further: Rett protein MeCP2 needed for proper adult neuron function

More information: Nature Genetics: www.nature.com/ng/index.html

Related Stories

Rett protein MeCP2 needed for proper adult neuron function

June 2, 2011
The protein MeCP2 is porridge to the finicky neuron. Like Goldilocks, the neuron or brain cell needs the protein in just the right amount. Girls born with dysfunctional MeCP2 (methyl-CpG-binding protein 2) develop Rett syndrome, ...

Developmental disease is recreated in an adult model

June 2, 2011
A new study published today in the journal Science has shown that the childhood disorder Rett syndrome, can be reestablished in adult animals by "switching off" a critical disease causing gene in healthy adult animals. The ...

Genomic architecture presages genomic instability: study

October 2, 2011
When cells divide normally, DNA gets copied perfectly and distributed among the daughter cells with an even hand. Occasionally though, DNA breaks during division and is rearranged, resulting in duplications or deletions of ...

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly identified genetic marker may help detect high-risk flu patients

July 17, 2017
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.