Mouse With Rett Syndrome May Provide Model for Testing Treatments, Understanding Disorder

Scientists funded by the National Institute of Child Health and Human Development (NICHD) have developed a new mouse model for Rett syndrome - a heartbreaking disorder which gradually robs apparently healthy infants of their language, mental functioning, and ability to interact with others. The research, by Huda Zoghbi, M.D. and colleagues, appears in the July issue of Neuron.

The researchers regard the mouse as an improvement over other animal models of the disease because the mice exhibit physical and behavioral characteristics that mimic Rett syndrome in humans much more closely than did earlier mouse models for the disorder.

"The generation of a strain of mice that have the features of Rett syndrome is an important advance in the quest to understand and prevent this devastating disorder," said Duane Alexander, M.D., Director of the NICHD. "By studying these mice, researchers will be able to learn more about the natural progression of Rett syndrome, as well as test medications and other treatments that might prevent or lessen the symptoms of the disorder."

The strain of mice developed by the researchers appeared normal for about six weeks, but then developed a progressive disease that closely mimics Rett syndrome in humans. For example, the mice developed tremors, problems with muscle control, seizures and curvature of the spine. They also appeared anxious and moved their front limbs in a motion similar to the constant hand-wringing seen in girls with Rett syndrome. Over time, the mutant mice appeared unkempt, most likely as a result of a lack of normal grooming. Their social interaction was impaired and normal mice actively avoided them.

To generate the mouse model of Rett syndrome, the researchers mutated, or altered, the MECP2 gene of male mice. The MECP2 gene, which is thought to be involved in brain maturation, is located on a region of the X chromosome, one of the two sex-determining chromosomes found in human cells. In a previous study, the researchers discovered that a large majority of Rett syndrome patients have abnormal MECP2 genes.

The protein produced by the MECP2 gene is the backbone in one of the elaborate networks of proteins needed to switch off a group of genes. In the absence of this genetic switch, certain genes fail to shut down, and excessive amounts of otherwise beneficial proteins are made. Experts believe that this, in turn, results in the brain and nervous system damage that causes the bizarre set of symptoms seen among Rett syndrome patients.

In humans, Rett syndrome occurs primarily among females, who have two X chromosomes, one inherited from each parent. Because each cell needs only one functioning X chromosome, roughly half the X chromosomes in genetically normal females are permanently switched off in a process called X chromosome inactivation. The X chromosomes are usually shut down in an apparently random pattern.

Like other females, girls with Rett syndrome have two X chromosomes. For this reason, they have some normally functioning copies of the MECP2 gene. Because of the random nature of X chromosome inactivation, some females with Rett syndrome have many cells in which the abnormal MECP2 gene is expressed, while others have few cells in which the abnormal gene is expressed. Scientists believe that the more cells a Rett syndrome patient has that express the abnormal gene, the more severe her symptoms will be.

While Rett syndrome occurs in roughly one in every 10,000 females, it is extremely rare in males. Because they have only one X chromosome, males with Rett-causing mutations have only the abnormal copy of the MECP2 gene and usually die before birth or in early infancy.

Although Rett syndrome in humans occurs primarily in females, the researchers used male mice to generate their mouse model of the syndrome, tampering with the MECP2 genes of the male mice in a way that was mild enough to allow the animals to survive. They did this in order to eliminate the effects of X chromosome inactivation.

"These mice are expected to be a more useful model for Rett syndrome than are previous models using female mice," said James Hanson, M.D., Chief of NICHD's Mental Retardation & Developmental Disabilities Branch. "Because they do not have a "backup" normal copy of the MECP2 gene, male mice have consistently more severe symptoms than female mice and have more uniform symptoms. This fact will allow researchers to better assess the effects of new medications and therapies in treating or preventing the symptoms of Rett syndrome."


The NICHD is part of the National Institutes of Health, the biomedical research arm of the federal government. The Institute sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site,, or from the NICHD Information Resource Center, 1-800-370-2943; E-mail

top of pageBACK TO TOP