A new study suggests targeting long genes could be a new treatment avenue for the devastating childhood disorder Rett Syndrome. The authors found that lack of the MeCP2 protein that is the hallmark of the disease causes subtle – but widespread – overexpression of long genes with functions important for the brain.

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Rett Syndrome is caused by the absence of MeCP2, a protein that regulates the expression of genes.

Rett Syndrome is a brain development disease that begins to show symptoms within the first 12-18 months. The disease, which almost exclusively affect girls, involves a loss of intellectual, social and motor skills, accompanied by autistic behaviors, such as repetitive movement of the hands.

While it is believed that Rett Syndrome does not severely damage cognitive function, the disease deprives children of speech, hand use, and often the ability to walk. As development ensues, it brings anxiety, seizures, tremors, breathing difficulties, and severe gastrointestinal problems.

While most children with Rett Syndrome survive to adulthood, they require total 24-hour care. There is currently no cure or effective treatment for the disease.

Scientists have known for years that Rett Syndrome is caused by the absence of MeCP2, a protein that regulates the expression of genes. But the big question that has been dogging them is which genes?

Michael Greenberg, Nathan Marsh Pusey Professor of Neurobiology at Harvard Medical School, Boston, MA, and colleagues may have discovered the answer. In their study – published in Nature – they suggest MeCP2 acts as a “dimmer switch” for long genes, and the absence of this fine control disrupts the normal expression pattern of genes, which leads to disease.

Every cell in our body has the same DNA containing the same collection of genes that provides the instructions for making a whole organism. Yet brain cells are different to heart cells and liver cells. This is because of differences in the patterns of their gene expression.

Patterns of gene expression influence cell development and function, and vary by genes being switched off, or switched on, and also by the intensity of their expression.

The average gene contains around 20,000 nucleotides – the A, T, C, G “letters” of the genetic code – but some can have as many as a million nucleotides.

For their study, Prof. Greenberg and colleagues analyzed various datasets of gene expression to look for a common theme. What they found intrigued them: the genes disrupted in Rett Syndrome tend to be the ones that are over 100,000 nucleotides in length.

When they analyzed the datasets and also looked at studies of different mouse regions, they found that when the MeCP2 protein is absent, long gene expression is increased.

Although the increase in expression is slight – between 3% and 10% – it applies to thousands of genes and so may have a significant impact on the function of the brain.

The team also carried out further tests and analyses to support their finding that Rett Syndrome is caused by overexpression of long genes due the absence of MeCP2.

For example, in autopsied brains of individuals with Rett they found that long genes were overexpressed. They also found the degree of increased long gene expression correlated with disease severity in mice.

And when they looked at the biological mirror image of Rett, the MECP2 Duplication Syndrome, the team found long genes are under-expressed.

Prof. Greenberg describes how he and his team feel about their findings:

MECP2 is one of the most complex problems I have worked on in my career. We persevere because I believe strongly that understanding how this protein works will help us to treat this devastating disorder. It’s gratifying to imagine that we, a basic science lab, may have opened the door to a novel way to think about treating Rett and MECP2 disorders.”

The results are exciting because there is a class of drugs called topoisomerase inhibitors that reduce the expression of long genes. Prof. Greenberg and colleagues have achieved encouraging results when they tested these drugs in cells missing the MeCP2 protein. They have now started to test the drugs in Rett mice.

The following narrated animation describes how the team went about their study:

The main funders of the study were the Rett Syndrome Research Trust and the National Institute of Neurological Disorders and Stroke (NINDS).

In June 2014, Medical News Today reported that a trial led by researchers at Boston Children’s Hospital of a Rett syndrome drug showed promising results. Children who received the drug for 4 weeks showed improvements in mood and anxiety, as well as easier breathing.