Scientists Create First Animal Model of Rett Syndrome

CAMBRIDGE, Mass. — Researchers from the Whitehead Institute for Biomedical Research have created the long-awaited animal model for Rett syndrome, one of the most common causes of mental retardation in females with an incidence of 1 in 10,000-15,000. The transgenic mouse model sheds much-needed light on the underlying mechanism of the disease and suggests a new reason for hope in the research toward therapies.

Rett syndrome, caused by a defective gene on the X-chromosome, is thought to have a lethal effect in males before birth or shortly after. Girls with Rett syndrome (and two copies of the X chromosome) are healthy babies who develop normally until six to eighteen months old. But then something goes terribly wrong–their health deteriorates and they begin to show symptoms such as loss of speech, loss of voluntary motor control, constant hand wringing, and seizures.

The work, published in the March 2001 issue of Nature Genetics from Rudolf Jaenisch and colleagues, suggests that the genetic defect underlying Rett syndrome has an effect not only during brain development before birth but has critical prolonged effects even after birth. Since it is easier to treat newborns than to correct defects in embryonic development, these findings may hold promise for future therapies.

In 1999, scientists from the Baylor College of Medicine in Houston, Texas, found that mutations in a gene called Mecp2 were responsible for Rett syndrome. However, the exact mechanism by which mutated Mecp2 brings about the mental deterioration was unknown.

The Jaenisch lab was able to use its expertise in transgenic technology to create mice in which the Mecp2 gene could be disrupted at any time during their development before or after birth. To the researchers’ surprise, male mice lacking Mecp2 did not die and showed a less severe syndrome. The male mice developed Rett-like symptoms, but survived to young adulthood, and females remained healthy well into adulthood. Similarities between the brains of mutant mice and Rett patients–small brains and small neurons–indicate that comparable brain and neuronal changes are occurring in both species. These mice, therefore, serve as good models for the disease.

Researchers previously hypothesized that Rett syndrome might result from widespread defects during embryonic development effecting the brain and possibly other organs. Though the Mecp2 gene is expressed throughout the body, the researchers found that the Rett-like symptoms in mice were caused by brain malfunction rather than problems of Mecp2 deficiency in the rest of the body.

Contrary to previous theories, the authors also indicate that the role of Mecp2 is not limited to the development of the brain before birth, but is also critical in the maintenance of mature neurons after birth. This suggests that therapeutic strategies could be aimed at preventing the development of postnatal defects in neurons, rather than at correcting neuronal deficiencies that existed before birth.