RETT SYNDROME ASSOCIATION UK

World Congress Paris 10 - 13 October 2008
 

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Research into Rett syndrome

There are many research projects in progress in the UK and abroad.  We provide updates on progress in research via our quarterly magazine, Rett News.  You may also wish to subscribe to the Rett Syndrome Research Foundation News Alert.  Email you full address to RSRFNews@feat.org.

A research team led by Dr Huda Y Zoghbi, a Howard Hughes Medical Institute investigator at Baylor College of Medicine in Houston, USA reported a very important new discovery in the October 1999 issue of US scientific journal Nature Genetics (http://www.nature.com/ng/press_release/ng1099.html).

This was painstaking and vital work and the whole team deserves our congratulations for this breakthrough. We applaud the part played by the International Rett Syndrome Association, our sister organisation in the USA.

The press in the USA and others have reported the discovery as finding the cause of Rett syndrome in a faulty gene called MeCP2 (pronounced meck-pea-two).   However, only a portion of the gene has been analysed so far and a lot more work remains to be done before we know the complete cause of the disorder.

What follows is a summary of Dr Zoghbi’s press release in October 1999:

Press Release from Baylor College

Dr Zoghbi said: "Finding the genetic cause of Rett syndrome has been the most challenging problem I’ve worked on. Usually we can map the location of a disease gene by studying the way the genetic defect is inherited in families. But Rett syndrome occurs sporadically more than 99 per cent of the time, so we had very few families to study where more than one member is affected with this neurological disorder."

When Dr Zoghbi began the search for the Rett syndrome gene 16 years ago, information from two families in which half-sisters developed Rett syndrome helped her to zero in on the X chromosome. "Because the girls had different fathers, we suspected that the disease gene was being transmitted from their mother."

She began hunting for the disease gene on the long arm of the X chromosome, which contains 2,000 to 3,000 genes. Finding more families with Rett syndrome enabled the researchers to narrow their focus to 1,000 candidate genes. A family in Brazil in which several girls had Rett helped researchers confine the hunt to 200 genes. The Zoghbi group analysed more than a dozen before finding the culprit, MeCP2.

The discovery that the Rett syndrome gene was on the X chromosome is interesting as most other forms of X-linked mental retardation, such as Fragile X syndrome, affect males. Unlike females, who have two X chromosomes, males have an X and a Y chromosome. Because males lack a ‘backup’ copy of the X chromosome which can compensate for a defective one, mutations in MeCP2 were thought to be lethal to the male foetus. Now we know that a small number of boys also have Rett syndrome.

"This gene is essential for life, not just for brain development," said Zoghbi. Girls with a mutated MeCP2 on one X chromosome are able to survive if they have a normal MeCP2 gene on the other X chromosome. But because the two X chromosomes are activated randomly, girls might have the normal MeCP2 gene active in some cells and the defective copy active in other cells. The defective MeCP2 leads to the development of Rett syndrome, and the severity of the disorder depends on the percentage of defective MeCP2 genes that are active.

Researchers have long known that MeCP2 is critical for the regulation of many other genes. Certain genes need to be activated at critical times during development and inactivated at others. MeCP2 is supposed to help turn off the expression of a number of genes. But in Rett patients, the defective MeCP2 might fail to keep those genes ‘silent’. If those genes remain active at inappropriate times, they could affect the function of nerve cells and alter normal development.

Dr Zoghbi is hopeful that knowing the genetic cause of Rett syndrome might make it possible to treat or prevent the disorder. "Because brain development continues long after birth, and symptoms of Rett syndrome do not develop for several months, there appears to be a window of opportunity during infancy in which we might be able to intervene to prevent further damage," Zoghbi said. "Now that we know the problem gene, we can explore the possibility of developing treatments which could be given in early infancy before symptoms appear."

A more recent  article on the pioneering research being done by  Dr Zoghbi on the genetics of brain disorders, from the Howard Hughes Medical Institute's quarterly magazine HHMI Bulletin can be found at  www.hhmi.org/bulletin/july2001/zoghbi/index.html