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“Rett syndrome is a genetic condition that occurs in 1 in 10 000 girls and is the most severe form of mental retardation after Down syndrome. It is most commonly caused by a mutation in a gene called MecP2, which is located on the X chromosome, but as research progresses we are finding other genes that are involved, such as CDKL5, mutations in which are common in girls who have a high level of seizures from a young age.
The mutations in the genes occur spontaneously along the entire length of the gene, there’s no cause for the mutations, they just happen. A mutation is like a faulty blueprint but instead of getting a building that won’t stand up you get a protein that doesn’t function normally, or doesn’t function at all.
Rett syndrome occurs in a wide spectrum of severity depending on how much functional protein is present, which depends on where the mutation exists along the gene. One interesting finding that has come about from studies on Rett syndrome is that if the mutation lies at the end of the gene it has less impact than if it occurs at the beginning of the gene.
In 2005 I received a Rett Syndrome Research Foundation grant to investigate the critical areas of MecP2 activity in the brain. I am still in the preliminary stages of research.
A few years ago scientists discovered that the mutation generally occurs in the DNA of sperm cells and because of this Rett syndrome affects only girls as they inherit the mutation on the X chromosome from their father. Boys of course inherit only a Y chromosome from their father and so do not inherit the MecP2 mutation.
We have been studying animal models that are missing the MecP2 gene entirely in various regions of the brain. What we hope to learn is where MecP2 activity is critical and exactly how it functions in the different regions of the brain. We are characterising the impact of MecP2 on behaviour including learning, memory deficits and mobility impairments. Scientists have identified 11 characteristics of Rett syndrome, now we need to investigate what is causing each of these characteristics.
The role and function of MecP2 in the brain is to silence genes, in other words to stop genes from being expressed and so preventing the proteins being produced. When MecP2 is mutated it can not perform this role. The characteristics of Rett syndrome are therefore due higher levels of various proteins than is normal. It is the effect of these proteins that causes the characteristics of Rett syndrome.
What we are now investigating is what genes are normally silenced by MecP2, what proteins are present in higher levels than they should be? You almost want to draw a family tree of what MecP2 controls, what proteins are produced that shouldn’t be and how they interact with the neurons in the brain. Once this is established we can then start to develop compounds to target the proteins or control the genes and hopefully prevent the characteristics of Rett syndrome from ever appearing. How this can be done is the next question."
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