July 18, 2002
Researchers Develop Mouse Model of Rett Syndrome
By studying gene mutations in patients with the complex set of
behavioral and neurological symptoms that accompany Rett syndrome,
Howard Hughes Medical Institute investigator Huda
Zoghbi and her colleagues at Baylor College of Medicine have
designed a mouse model that faithfully recapitulates the disease down
to its distinctive hand-wringing behavior.
The development of the mouse, reported in the July 18, 2002 issue of
the journal Neuron, provides a springboard into the study of
Rett syndrome, the leading cause of mental retardation in girls.
“As development progresses, what we encounter -- our experiences -- may also change how the brain responds. This may account for individual variation in disease severity.”
Huda Y. Zoghbi
First recognized as a syndrome in the 1980s, the disorder affects
one in 10,000-15,000 girls. It is particularly devastating for families
with affected children because infants are seemingly normal at birth
and achieve the usual developmental milestones for the first few months
of life. Then, as the infant reaches toddlerhood, a sudden and dramatic
decline in physical and mental capabilities takes hold, accompanied by
onset of seizures, irregular breathing, awkward gait, and
hand-wringing. “I know of no other neurological disease that
gives this distinctive stereotypic behavior — this hand-wringing these
girls do basically all the time they are awake,” said Zoghbi.
“With this mouse model we can now ask, ‘Why is
that?’”
Zoghbi has been studying Rett syndrome since the mid-1980s, when she
first encountered patients with the disorder as a neurology fellow and
decided to search for the gene responsible for the disorder. She
reasoned that the gene must be on the X chromosome, the female sex
chromosome, and it must also be essential because there had been no
males reported to have the syndrome. (Since males have only one X
chromosome, mutations that knock out the gene’s function could be
lethal at an embryonic stage.) In females, there are two copies of the
X chromosome, but in each cell only one of the two X chromosomes is
active. The scientists reasoned that if enough cells are
“normal,” they can compensate for the mutated gene.
After 14 years of searching, a scientist in Zoghbi’s lab found
that a gene called MECP2 was mutated in the Rett Syndrome
patients they studied. Earlier research suggested that the MeCP2
protein was responsible for making sure that genes the cell has marked
with a molecular tag, called a methyl group, are silenced. The MeCP2
protein latches on to these methyl groups and prevents them from being
translated into protein.
How MeCP2’s molecular role translates into a neurological
disorder is still not clear. Ever since a diagnostic test for the gene
mutation was developed, however, there has been a flood of new
information about the prevalence of the disorder. This information
reveals that mutations in the MECP2 gene can take a wide variety
of forms.
“We now know of cases of classic autism and schizophrenia that
are caused by mutations in this gene,” said Zoghbi. “The
clinical spectrum is so broad that we don’t know the true
prevalence of this mutation.” She estimates that the mutation may
be twice as common as is currently thought, with perhaps one in 10,000
children affected.
What is clear so far is that the MECP2 gene, which resides at
the end of the long arm of the human and mouse X chromosome, plays a
vital role in fine-tuning the developing nervous system during a
crucial stage when infants are learning to sit up, walk, and begin
language acquisition, said Zoghbi.
To understand the molecular details of what goes wrong, the
scientists first needed to create a mouse model of the disorder. The
first attempt at a mouse model, in which the MECP2 gene was
deleted completely, resulted in severe disease and early death. Zoghbi
and her colleagues sought to create a model that would more closely
mimic the progression of the human disorder. So, they studied the
various mutations that had been found in patients to design a mutant
mouse that would produce a partially functional protein. The result was
a mouse that mimics many of the aspects of the disease observed in
humans.
Using the mouse model, the scientists will probe how the MeCP2
protein affects brain function at a crucial developmental stage.
“The second part of the story is really in discovering what this
protein is doing in the brain,” said Zoghbi. “It may be
that at a certain developmental stage, the brain suddenly requires the
function of this protein. In humans, by birth a lot of the hardwiring
has already happened. Infancy is a critical time as life experiences
refine synaptic function and strengthen synapses. Experiences fine tune
the brain. Perhaps more complex tasks require the input of this protein
and its loss is now instrumental. Things fall apart and people regress.
Perhaps key genes that are important at certain times are not put in
place. We don’t know the mechanism but having this mouse model
will allow us to ask these questions.”
Zoghbi is hopeful that studying the mouse model will also have
implications for treatment of patients diagnosed with Rett Syndrome.
“As development progresses, what we encounter — our experiences
— may also change how the brain responds. This may account for
individual variation in disease severity,” she said. “It
may be that enrichment of the environment or exposure to certain
stimuli may give affected children more milestones. I could envision
that with interventional studies in mice, we may identify pathways that
could lead to behavioral or pharmacological approaches that may provide
at least symptomatic relief.”
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