A study funded by the National Institutes of Health (NIH) has transformed scientists' understanding of Rett syndrome, a genetic disorder that causes autistic behavior and other disabling symptoms.
Until now, scientists thought that the gene behind Rett syndrome was an "off" switch, or repressor, for other genes. But the new study, published in "Science", shows that it is an "on" switch for a startlingly large number of genes.
Rett syndrome is caused by a deficiency of the MECP2 gene. It occurs almost exclusively in girls, robbing them of language, cognitive and fine motor skills around the time they are learning to walk. Having extra copies of MECP2 can also cause Rett-like symptoms.
By manipulating the number of copies of the MECP2 gene in mice, the authors of the new study found that it controls thousands of other genes, suppressing some, but activating most.
The research was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of NIH.
"This study simultaneously upends prevailing ideas about the disease process in MECP2-related disorders, and hints at new therapeutic strategies," says NIH Director Elias Zerhouni, M.D.
Rett syndrome occurs predominantly in girls because the MECP2 gene is located on the X chromosome. In boys, who have only one X compared to girls' two, a deficiency of MECP2 tends to cause death during infancy.
Girls with Rett syndrome tend to develop normally until about one year of age, and then regress in their language, cognitive and motor skills. They lose the words they have learned, as well as their skilled hand movements, which become replaced by repetitive wringing and clapping. Other common features include seizures, stunted growth and small brain size, mood disturbances, and sleep problems.
Duplications of MECP2 have been linked to another syndrome, which can cause Rett-like symptoms, and sometimes severe mental retardation, in boys.
MECP2's dual roles in gene repression and activation were "a total surprise," says the lead author of the new study, Huda Zoghbi, M.D., a professor at Baylor College of Medicine in Houston and an investigator of the Howard Hughes Medical Institute.
Dr. Zoghbi led the team that first linked MECP2 deficiencies to Rett syndrome in 1999, also an NIH-funded effort. Many lines of evidence pointed to the MeCP2 protein as a gene repressor, and that is how experts in the field, including Dr. Zoghbi, have defined its function for the past 10 years.
Dr. Zoghbi did not intend to question that definition. She was interested in comparing Rett syndrome and MECP2 duplication syndrome, and in adding to the list of the few genes known to be regulated by MECP2.
Toward that end, she and her team analyzed gene activity patterns in the brains of mice with a MECP2 deficiency and in mice with a MECP2 duplication (MECP2+).
Previous studies had revealed only subtle differences between the brains of normal and MECP2-mutant mice, but those studies measured gene activity throughout the brain. Dr. Zoghbi's group focused on a brain region called the hypothalamus, which is known to produce hormones that influence growth, mood, and the sleep-wake cycle - all of which typically become derailed in Rett syndrome.
Their analysis revealed nearly 2600 genes that are misregulated in both mouse models, with opposite patterns. The activity of about 2200 genes dropped in MECP2-deficient mice and spiked in MECP2+ mice, indicating that MECP2 is an activator for those genes. About 400 genes showed the reverse pattern, indicating that MECP2 is a repressor for those genes.
In other experiments, the researchers confirmed that the MeCP2 protein binds directly to several of the target genes. They also found evidence that MeCP2 collaborates with another protein known to serve as a gene activator. Among the genes activated by MeCP2, the researchers found many that encode neuropeptides, proteins that are secreted by nerve cells.
All of these results raise a number of challenges and opportunities for future research, Dr. Zoghbi says. Researchers could design effective therapies for Rett syndrome and MECP2 duplication syndrome by aiming at MeCP2's target genes, but first they would have to know which target genes are most relevant to neurological function. Also, given that the two disorders have opposite gene activity profiles, they might not respond to the same therapies.
The ideal therapy would aim closer to MECP2 itself, Dr. Zoghbi says.