Nolan Redetzke ’18 and Karissa Gawronski ’18

Imagine you have just welcomed a lovely baby girl into the world, be it your own daughter, niece or sister. She appears happy (despite the common initial tears) and the doctors announce her to be healthy. For a few months, she continues to grow and develop successfully. However, just after her first birthday, you notice that she starts taking less pleasure in playing with her once favorite toys. Additionally, she does not appear to be sitting or crawling as your family friend’s child, who is of similar age. A year or so later, the girl appears to have difficulties breathing, has begun displaying bizarre hand motions, like repeatedly moving her hands to her mouth and wringing them, and you notice her head appears smaller than the average child her age. She is not communicating as much as she used to. A few years later, she begins having severe motor deficits as well as seizures, however, she showcases increased alertness and attention. Finally, you notice that the girl struggles with reduced mobility, muscle weakness, but has an increase in eye gaze. These symptoms represent issues that one may encounter during the four stages of Rett Syndrome, a cognitive disorder (with features of autism) afflicting approximately 1 in every 10,000-15,000 girls worldwide1.

Growing up, most of us have probably heard about the nature versus nurture debate: do our genetics or our surrounding environment and experiences shape who we are? Current research suggests that it is a bit of both, and perhaps more surprisingly, that our daily experiences may actually work to change our genetics. This information regards the idea of something called epigenetics. Our body contains a LOT of DNA, which encodes the information within our cells and makes us who we are. It does this by encoding proteins, which are like tiny machines inside of the cell; each carrying out a different function. Specific areas of DNA match up to specific proteins, or little machines. If we were to line up all the DNA in all of our cells end-to-end, it would travel from the Earth to the Sun…hundreds of times2! However, we do not necessarily use all of this DNA at once. We only need certain proteins at specific times; just as you put you only bring out your sweater when the weather gets colder. Proteins are also produced in different amounts; just like roads have different speed limits. Some are like interstates and are highly produced and used frequently. Some are like city roads, which are slow and don’t produce a lot of protein. DNA is sometimes physically changed through adding a methyl group, or a chemical tag, which acts like slowing down the speed limit on that road, making it less used. Our environment can impact the amount of methyl groups present, thus determining how frequently proteins are produced.

Rett syndrome is most commonly caused by a mutation in the protein MeCP2. It is only present in girls because MeCP2 is found on the “X” sex chromosome (a part of the DNA), which girls have two copies of and boys have one. Since females have two copies of the X chromosome they, are able to survive with one functioning and one mutated copy of the protein; but males die early from altered brain structure and function, issues with moving, and breathing problems, since they only have the mutated version3.

Unique experiences early in life cause the body to respond in different ways; from something as simple as your nose turning red in the cold,  to something as complex as learning to identify your parents. At a molecular level these changes are brought about by genes, or the parts of the DNA which encode proteins, being expressed or used at different levels. As babies grow and mature, their bodies realize that they are not using some genes as much and add methyl groups to repress those genes. This is like a road that shouldn’t be used a lot getting a lower speed limit. Cells use different amounts of methylation on genes to regulate the amount of specific proteins produced and stay healthy; just like roads have different speed limits to maintain a good flow of traffic. These changes are also long-lasting and maintained into adulthood, just like city roads likely maintain their speed limits for years.

Researchers have found that protein DNA methyltransferase 3A is primarily responsible for adding the methyl groups to DNA that is used less. So DNMT3A is like the person who determines which roads are not used as much and puts up lower speed limits on them. They determined this by removing DNMT3A from mouse brains and then comparing the amount of methylation present compared to control animals with the protein. Without this protein the mice had a lot less methylation and many proteins were produced in different amounts.

In Rett syndrome, proteins are produced in more and more unnatural amounts over time. This causes problems that slowly build upon one another as children develop and thus why symptoms do not appear until one year of age. In a majority of Rett syndrome cases the cause is linked to a mutation in the protein MeCP2. It acts like a stoplight on a road, which further controls traffic flow or the amount of protein produced. You wouldn’t find a stoplight on an highway, you only see them on roads with lower speed limits. Similarly MeCP2 can only work when DNA has already been methylated; in fact it binds to the methyl groups directly. Having Rett syndrome would be like having a city without stoplights, traffic flow gets all messed up and the city develops traffic problems over time as roads are used in unnatural ways4.

In Rett syndrome the ability to learn and have the brain grow is decreased. This is because some important proteins in this process are no longer produced as much; one specific one is called Brain-derived neurotrophic factor (BDNF), a brain chemical that cells use to communicate to one another. Rett syndrome patients have mutated MeCP2, which we said acts as a stoplight. Researchers have found that the mutated version acts like a stoplight that is always red, constantly stopping the protein from being produced5. Thus, no traffic is flowing through this intersection, just as no BDNF is being made. Without BDNF, brain cells can’t change as easily, an essential part of learning and development.

So how can we combat the detrimental effects of such a problematic disorder? Although currently there no available treatments to cure Rett syndrome, there have been a few studies investigating possible therapies for the symptoms. One such study looked at changing levels of a protein that reduces hormone signalling, called Protein tyrosine phosphatase 1B (PTP1B), by using PTP1B inhibitors in mice. Increased levels PTP1B lowers BDNF signaling, which leads to less learning and development6. Once again, we know that BDNF signaling is in charge of communication and neuronal development, so if it is lowered, then less development of the nervous system will occur. A group of researchers at the Cold Spring Harbor Laboratory injected PTP1B inhibitors into a group of male mice exhibiting Rett-like characteristics. They found that this infusion dramatically lengthened the lifespan of the male rats. Additionally, the inhibitor improved the cognitive and motor deficits in mature females6. So, by inhibiting PTP1B, they found they were able to increase BDNF signaling that is normally reduced in Rett Syndrome.This information may be helpful in discovering possible treatment or therapy options in humans.

Unfortunately, since there is still no concrete cause for the mutation behind Rett syndrome, there are no current prevention tactics or known cure. Animal studies have helped increase our understanding for the disorder, however we need to make sure that we do not necessarily generalize all of the findings to humans, as humans have some differences in anatomy and physiological responses. The fact that there are numerous types of MecP2 mutations that lead to variations of Rett syndrome, only makes this more difficult. Additionally, less than 1% of cases are inherited, alluding to the spontaneous nature of this mutation1. However, in some families that have a member or members suffering from Rett syndrome, genetic testing has been shown to reveal other members with a mutation of their MecP2 gene, although without symptoms1. The knowledge that genetic testing may aid in predicting one’s risks for Rett syndrome, in conjunction with possible symptomatic treatments, may eventually lead us to finding a way to eventually prevent and/or cure Rett syndrome. But until that time, people afflicted with Rett syndrome have been known to live into their fifties, with the support of their families, physical therapy, and symptomatic drug therapy.


  1. Rett Syndrome Fact Sheet. (n.d.). Retrieved March 20, 2018, from
  2. Annunziato, A. (2008) DNA Packaging: Nucleosomes and Chromatin. Nature Education 1(1):26
  3. Luikenhuis, S., Giacometti, E., Beard, C. F., & Jaenisch, R. (2004). Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proceedings of the National Academy of Sciences, 101(16), 6033-6038. doi:10.1073/pnas.0401626101
  4. Gabel, H. W., Kinde, B., Hume, S., Gilbert, C. S., Harmin, D. A., Kastan, N. R., Hemberg, M., Ebert, D. H., and Greenberg, M. E. (2015). Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature, 522, 89-93.
  5. Stroud, H. et al. “Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States.” Cell 171.5 (2017): 1151-1164. CellPress. Web. 20 Mar. 2018.
  6. Zhou, Zhaolan et al. “Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation.” Neuron 52.2 (2006): 255–269. PMC. Web. 20 Mar. 2018.
  7. Krishnan, N., Krishnan, K., Connors, C. R., Choy, M. S., Page, R., Peti, W., . . . Tonks, N. K. (2015). PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. Journal of Clinical Investigation, 125(8), 3163-3177. doi:10.1172/jci80323

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