The Rett gene -- a rogue activator

May 29, 2008

In 1999, when Dr. Huda Zoghbi and her Baylor College of Medicine colleagues identified a mutation of the gene MeCP2 as the culprit in Rett syndrome, a neurodevelopmental disorder, the discovery was only the prelude to understanding a symphony of neurological missteps.

Unraveling the story of MeCP2 demonstrates the finicky nature of neurons that work best when the recipe for the proteins affecting them is followed exactly. Zoghbi and her collaborators describe the role MeCP2 plays in the brain in a report that appears in the current issue of the journal Science.

“Whether you lose the protein or gain too much, the symptoms in the brain overlap quite a bit,” said Zoghbi, who is a BCM professor of pediatrics, neurology, neuroscience, molecular and human genetics and a Howard Hughes Medical Institute investigator. “The brain is very sensitive to its physiological equilibrium.”

Yet the brain or neurons in it can demonstrate a problem with only a limited range of symptoms – autism, seizures or mental retardation.

“The symptoms are those of an unhappy neuron,” said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.

Zoghbi and her colleagues found that MeCP2 is a key regulator that can turn on and off genes that govern activities in the neurons of the hypothalamus. While MeCP2 can turn off a gene, it is more likely to turn it on.

As infants, girls with Rett syndrome seem normal for at least six months. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Many of their symptoms mirror those of autism. Zoghbi’s laboratory was the first to identify a mutation in the MeCP2 gene that results in too little of this protein, causing girls to develop Rett. Boys who suffer from a disorder linked to an excess of MeCP2 have impaired motor function, seizures and mental retardation with autism-like behavior.

In trying to find out how the alterations in MeCP2 affect the brain, the scientists began their studies in the hypothalamus because symptoms of Rett syndrome such as anxiety, sleep disturbance and slowed growth can all be attributed to problems in that part of the brain. Previous studies of the whole brain proved inconclusive, and by targeting a very specific area of the brain, Zoghbi and her collaborators hoped to zero in on the problem.

“Loss of function of the MeCP2 gene causes Rett syndrome,” said Maria Chahrour, a BCM graduate student and first author of the report. Doubling or tripling MeCP2 levels causes other neurological disorders. To better understand the protein, the scientists decided to study mice that either lacked MeCP2 or had too much of it.

They dissected the hypothalamus in both kinds of mice and looked at changes in the genes compared to the same genes in normal mice.

“There are thousands of genes changed by MeCP2,” said Chahrour. In both the mice who had no MeCP2 and those who had too much of the dysfunctional gene, they found changes in expression of thousands of genes. Surprisingly, they found that in at least 85 percent of the genes, MeCP2 turned the gene on. In fact, they found that it associates with CREB1, another gene tasked with turning on genes.

Interestingly, although the two diseases share many features, having no protein versus having too much caused opposite effects on gene expression, suggesting again that “the symptoms are those of an unhappy neuron,” said Zoghbi. Yet as the MeCP2 studies show, these symptoms can have different causes. That fact may mean that what outwardly appears to be the same disease could have very different beginnings and require wholly different treatments.

“Because MeCP2 regulates thousands of genes, it does not make sense to target each of them individually in designing treatments,” Chahrour said. “We are going to have to find a therapeutic strategy that can bypass MeCP2 and restore the normal order in the brain,” she said.

Source: Baylor College of Medicine

Explore further: Test reveals potential treatments for disorders involving MeCP2

Related Stories

Test reveals potential treatments for disorders involving MeCP2

August 23, 2017
Having twice the normal amount of the protein MeCP2, a condition called MECP2 duplication syndrome, causes severe progressive neuropsychiatric disorders that include intellectual disability, autism spectrum disorders, motor ...

Discovery fuels hope for Rett syndrome treatment

August 23, 2017
Vanderbilt University researchers have relieved symptoms of Rett syndrome in a mouse model with a small molecule that works like the dimmer switch in an electrical circuit.

First pre-clinical gene therapy study to reverse Rett symptoms

August 20, 2013
The concept behind gene therapy is simple: deliver a healthy gene to compensate for one that is mutated. New research published today in the Journal of Neuroscience suggests this approach may eventually be a feasible option ...

Insights into neurons that cause symptoms of Rett syndrome could guide new therapy search

June 28, 2016
Two studies in mice from Baylor College of Medicine, Texas, reveal new insights into neurons that mediate symptoms typical of the postnatal neurological disorder Rett syndrome.

Study finds two genes affect anxiety, behavior in mice with too much MeCP2

January 8, 2012
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 ...

Normalizing levels of MeCP2 in mouse model of MECP2 duplication syndrome restores neurological dysfunction

November 25, 2015
Gene duplications are a common cause of intellectual disabilities and autism as well as various other neurological disorders. In a new study that appears online in the journal Nature, Dr. Huda Zoghbi, professor of molecular ...

Recommended for you

Exploring disease predisposition to deliver personalized medicine

October 23, 2017
Geneticists from the University of Geneva have taken an important step towards true predictive medicine. Exploring the links between diseases and tissue-specific gene activity, they have been able to build a model that constitutes ...

Maternal diet may program child for disease risk, but better nutrition later can change that

October 20, 2017
Research has shown that a mother's diet during pregnancy, particularly one that is high-fat, may program her baby for future risk of certain diseases such as diabetes. A new study from nutrition researchers at the University ...

New gene editing approach for alpha-1 antitrypsin deficiency shows promise

October 20, 2017
A new study by scientists at UMass Medical School shows that using a technique called "nuclease-free" gene editing to correct cells with the mutation that causes a rare liver disease leads to repopulation of the diseased ...

Researchers find evidence of DNA damage in veterans with Gulf War illness

October 19, 2017
Researchers say they have found the "first direct biological evidence" of damage in veterans with Gulf War illness to DNA within cellular structures that produce energy in the body.

Researchers drill down into gene behind frontotemporal lobar degeneration

October 19, 2017
Seven years ago, Penn Medicine researchers showed that mutations in the TMEM106B gene significantly increased a person's risk of frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in those ...

Genetic variants associated with obsessive-compulsive disorder identified

October 18, 2017
(Medical Xpress)—An international team of researchers has found evidence of four genes that can be linked to obsessive-compulsive disorder (OCD). In their paper published in the journal Nature Communications, the group ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.