Researchers Find Rett Syndrome Gene is Full of Surprises

A new study has transformed scientists' understanding of Rett syndrome, a genetic disorder that causes autistic behavior and other disabling symptoms.

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 cause Rett-like symptoms as well, in a condition called MECP2 duplication syndrome.

Until now, scientists thought that the gene behind Rett syndrome was an “off” switch, or repressor, for other genes. A team led by Dr. Huda Zoghbi, a Baylor College of Medicine professor and Howard Hughes Medical Institute investigator, set out to explore the role of MECP2 by manipulating the gene in mice. The work was funded by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), among others.

As they reported in Science on May 30, 2008, Zoghbi 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 had measured gene activity throughout the brain. Zoghbi's group focused on the hypothalamus, the brain region that produces hormones that influence growth, mood and the sleep-wake cycle—all of which typically become derailed in Rett syndrome.

Their analysis revealed that the activity of about 2,200 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. MECP2's dual roles in gene repression and activation were “a total surprise,” Zoghbi says.

In other experiments, the team confirmed that the MeCP2 protein binds to several of the target genes. They also found evidence that MeCP2 interacts 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.

Zoghbi, who led the team that first linked MECP2 deficiencies to Rett syndrome in 1999 (also an NIH-funded effort), says that these results raise a number of challenges and opportunities for future research. Researchers could potentially design therapies for Rett syndrome and MECP2 duplication syndrome by aiming at MECP2 itself or at MeCP2's target genes.

“We know that the MeCP2 protein is important for orchestrating gene expression in neurons,” Zoghbi says. “To treat the disease, we may need to find a way to re-orchestrate gene expression. The challenge is to identify the immediate lieutenants of MeCP2, and co-opt them to take over when MeCP2 is not working.”