NIH Researchers Find That Rett Syndrome
Gene is Full of Surprises
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 today 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,
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
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
"We know that the MeCP2 protein is important for orchestrating
gene expression in neurons," Dr 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."
is the nationís primary supporter of biomedical research on the
brain and nervous system. NICHD (http://www.nichd.nih.gov/)
sponsors research on development, before and after birth; maternal,
child, and family health; reproductive biology and population issues;
and medical rehabilitation. For more information on Rett syndrome,
visit http://www.ninds.nih.gov/disorders/rett/rett.htm or http://www.nichd.nih.gov/health/topics/Rett_Syndrome.cfm
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Chahrour M et al. "MeCP2, a Key Contributor to Neurological
Disease, Activates and Represses Transcription." Science,
May 30, 2008.