Laura Heckman, Baylor College of Medicine
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Rett syndrome is a neurodevelopmental condition linked to a gene called MECP2, which controls the activity of other genes by binding to DNA and then suppressing their expression. But which of these two processes are key to causing the disease and a related syndrome caused by having additional copies of the MECP2 gene. Laura Heckman has cleverly solved the puzzle by making mice that carry a working healthy copy of the MECP2 gene alongside an altered copy that lacks either the DNA binding activity or the gene repressing activity, as she explains to Chris Smith...
Laura - So, in our lab, we study a gene called MECP2 and it turns out that itís really important because we see that if you have too little of the gene, in humans, you see Rett syndrome which is a progressive neurological phenotype. Girls typically had this disorder and theyíll develop normally for the first 6 to 18 months of life. And then you'll actually see developmental stagnation and then regression. So, theyíll lose purposeful hand movement. Theyíll develop anxiety and other autistic features, mostly late motor deterioration. On the other hand, if you had too much MECP2 then this presents in different disorder called MECP2 duplication syndrome. What's interesting about this is that itís also a progressive neurological disorder. We see some overlap with the phenotypes such as autistic features. But itís also distinct and that we see spasticity and seizures, and infantile hypotonia which isnít seen in Rett syndrome.
Chris - What exactly does this gene do?
Laura - So, we know a bit about what MECP2 does. Its level increases highly throughout development and so far, what's really known is that there's two main domains. One, binds DNA and then the other represses other genes. And so, I think that these work together to regulate other genes that are expressed during development and then throughout adulthood.
Chris - So, giving that important role its ability to influence many other genes, itís not surprising that it probably has an impact on the way that the brain develops and functions. But then the question is, well why does too much of it have this effect and why does too little of it have an effect? How can you disentangle the two?
Laura - Exactly and thatís one of the questions that we aim to address Ė to try to figure out what MECP2 is doing in both Rett syndrome and MECP2 duplication syndrome. We chose to study two point mutations in the gene Ė one, which affects the domain which binds DNA and one which affects the domain responsible for repressing genes. And so, when we look at these, when itís the only copy of MECP2, we can get an idea of how it affects the function of MECP2. On the other hand, if we express it with an extra copy of MECP2, then we can get an idea of which domains are required in order to see these toxic phenotypes.
Chris - So, you can dissect apart which of the two ends of the molecule is involved in each of the two phenotypes, can't you?
Laura - Exactly, yes.
Chris - And go on then, spill the beans. When you do this, what do you see?
Laura - So, when we do this, we see that we actually need both domains completely intact in order to see the duplication phenotypes. This is really interesting since a lot of previous hypothesis thought that maybe just the one domain was responsible and the other didnít really play a large role.
Chris - So, you need both ends of the molecule to be active in order to do the job of causing the syndrome if you have the duplication problem. But what about if youíve got the deletion or the initial mutation just in one copy? What about that phenotype?
Laura - When in the Rett syndrome context, we also find that completely messing up one of the domains will lead to an null phenotype on a very severe actually. So, that means that whatever additional function the repression is handling, itís not enough to overcome the lack of binding to DNA. On the other hand, when we looked at the repression domain, we actually found a couple interesting things. We saw milder phenotype. So, they still had many of the same phenotypes that weíre used to seeing, but not as strongly. We also found an additional function for this end of the protein. So, we initially thought that it just interacted with other proteins in order to request transcription. But it turns out that it can also bind DNA.
Chris - What do you think the implication of that is? What does that actually translate into in terms of our understanding of this process?
Laura - So, I think there are a few important takeaways from this. One is that we now see that in order for MECP2 duplication syndrome to occur, that you need the entire protein to be functional. The second is that we see these differences in different mutations that have various effects on the individuals. So for example, the previous models, many of them die very early on until itís hard to study and hard to figure out how to help the mice and therefore, the patients. So, these new mice are better so that we can have longer outcomes for potential therapies. Additionally, and itís also interesting that putting in a normal copy of MECP2 can rescue many of the Rett syndrome phenotypes. And so, this can also become a viable potential therapy in the future...