Photo of Rett Syndrome pediatric patient UC Davis Genome Center research aims to help children like Angela, who have Rett Syndrome.

Rett Syndrome is a relatively rare neurodevelopmental disorder with a known genetic cause — a mutation in an X-linked gene called MECP2. For years, scientists have been constructing a model to explain how this mutation disrupts the normal genetic machinery of brain cells. The completion of the Human Genome Project and the resulting microarray technology has now allowed UC Davis researchers to test that model. What they found surprised them and will undoubtedly lead to a more accurate understanding of Rett Syndrome genetics and the role of the MECP2 protein.

"This is the first time anyone has looked genome-wide to see where the protein is binding," explained Janine LaSalle, a professor of microbiology and immunology at UC Davis School of Medicine and senior author of the study. "When you open up your field of view to the whole genome, the model does not hold up."  

The current study, which appeared in the December 4 issue of the Proceedings of the National Academy of Sciences, is a result of a collaboration between LaSalle and Peggy Farnham, a professor of microbiology and immunology at the UC Davis School of Medicine and at the UC Davis Genome Center. Farnham is a specialist in the emerging field of epigenomics, which applies microarray technology to study changes in gene expression that are not dependent on changes in the DNA sequence of the gene. Epigenomics, for example, includes the study of where proteins bind along a chromosome.

"These epigenetic factors are harder to study, but their potential impact is becoming more appreciated," said LaSalle, who is also a member of the Rowe Program in Human Genetics. The power of the genomic approach, she said, was in the ability to survey all 35,000 known genes of the human genome. "We would not have tried to counter this model if we had gotten unexplained results when looking at one gene. But none of the genes fit the model, so we feel more confident in saying that it is time to re-examine the field."

Photo of Janine LaSalle"These epigenetic factors are harder to study, but their potential impact is becoming more appreciated."
— Janine LaSalle, senior author of the study

According to a widely held theory, the protein coded for by MECP2 in neurons was believed to work by blocking other molecules called promoters which are involved in the initiation of gene transcription.

"Contrary to our expectations, we found that it is not sitting on the promoters of silent genes, but between genes and on active genes," she said.

Autism researchers are paying particular attention to the genetics of Rett Syndrome because of the autistic-like symptoms exhibited by those with the disorder.

Photo of another Rett Syndrome pediatric patient Maiya, a Rett Syndrome patient.

"The hope is that this work can help us understand disorders that fall under the greater heading of autism," she said. There is additional relevance to the field of autism because recent studies suggest that Rett Syndrome may be the first autism spectrum disorder to be cured. Last year, researchers reported that gene therapy to restore the protein made by MECP2 resulted in partial reversal of symptoms in mice.

Rett syndrome is a childhood neurodevelopmental disorder characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures and mental retardation. It affects females almost exclusively, with symptoms appearing between the ages of 6 and 18 months of age.

LaSalle and her colleagues are now working on further genomic analyses that they hope will shed light on the true nature of the MECP2 protein. LaSalle believes the protein is important in translating environmental signals to gene expression changes at a time when neurons are maturing. Regression in development of girls with Rett syndrome supports this theory.

"It's almost like the neurons get stuck there waiting for this factor and they are not able to make the more complex connections to other neurons without MECP2," she said.

Understanding the role of MECP2 is important to moving the field of Rett Syndrome genetics forward, LaSalle said. "We would also like to move to the point of therapies for this disorder, and I think this new understanding will bring us closer to that goal," she said.

To learn more about Rett Syndrome, click on this link.

Cover photograph: Jennifer, Jillian and Justin Endre.