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 Neurological Research Institute at Texas Children's Hospital.
MeCP2 is a "Goldilocks" in the protein world. When the protein is
lacking or defective, girls develop the neurological disorder 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
behavioral deficits 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 human genetics at BCM and first
author of the paper. "We first identified the mouse model 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 genes 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 protein 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 anxiety associated with the
duplication syndrome.
