Rett & MECP2 Duplication are Epigenetic Syndromes

lightbulbWhile Rett syndrome and MECP2 Duplication Syndrome are typically discussed as genetic syndromes, they are both examples of a small subset of genetic syndromes called epigenetic syndromes. During most or the 20th Century scientists believed that genetics determined most of our health and behavior in ways that were relatively unchanging throughout our lives. During the second half of the 20th Century, most scientists believed that this genetic information was immutably coded in our DNA. During the last decade of the 20th Century, however, this view was modified with the recognition of epigenetics.

Epigenetics is the process by which DNA is modified by an individual’s interaction with his or her (internal and external) environment. This happens as interaction with the environment switches various combinations of genes on or off.

I first became really interested in epigenetics when I was researching the connection between violence and disability in the 1990s. Data seemed to show that survivors of emotional or sexual child abuse frequently had physical and behavioral effects even though there was no physical injury and could not be explained simply by direct psychological effects. How was that possible?

After a lot of searching, I began to find an answer in epigenetic studies. One that stood out for me was a study from McGill University. It demonstrated that lab mice who gave affectionate maternal care to their babies, passed this on from generation to generation genetically. Those that gave less affectionate care to their babies also passed that on. While this appeared to be genetically transmitted, the researchers demonstrated that the affectionate caring was passed on even when the babies were not biological offspring of the mothers. The DNA of the babies was somehow modified in some way by affectionate maternal care, and once modified their behaviour was changed in adult life.

MECP2: The Goldilocks Master Gene

We now know that much of this DNA modification process takes place through a process called methylation. The DNA structure remains pretty much the same throughout life, but methylation adds methyl groups to various specific genes and in doing so turns some genes on and turns others off. One of the major players in this process is the MECP2 gene, it produces the MeCP2 protein that can be recruited to DNA sites to turn specific genes off (and indirectly turn others on). In case anyone is wondering, it it got its name MECP2 because it is the gene that instructs cells to produce the MeCP2 protein, and MeCP stands for Methyl CpG-binding Protein. CpG is a particular base combination that appears frequently in DNA, and binding a methyl group to a CpG site silences some genes while increasing activity of others. By selectively binding methyl groups to the right genes, our bodies regulate how individuals respond to internal and environmental conditions. MECP2  has been called a master gene because it controls or influences many (likely thousands) of other genes. In fact, many of the genes regulated by MeCP2 genes are regulators of other genes. As such, it is a true master gene or “boss of bosses.”


MECP2 also has been called a Goldilocks gene because both too much activity (“this porridge is to hot”) or too little activity (“this porridge is too cold”)  cause problems. MECP2 duplication syndrome results in too much activity and Rett syndrome results in too little.

The Same or Different?

Among the many mysteries posed by Rett and MECP2 duplication syndromes is why these two conditions that are polar opposites produce many of the same effects? One might reasonably expect the effects of these two disorders to be quite different. After all, when the porridge is too hot it burns your mouth, when its too cold, it’s just unappetizing. Nevertheless, both too much and too little MECP2 activity both seem to produce symptoms of autism. Interestingly, many of the other genetic syndromes that produce autism are also involve genes that play a regulatory role in the epigenetic process. Perhaps, at least a part of the answer lies in that study of lab mice described above. It showed how epigenetic processes regulate underlying genes to encode the social environment. Both Rett and MECP2 duplication syndrome may simply make these epigenetic processes less responsive to social experience.

Of course, the same underesponsive epigenetic system would also result in a weaker response to biological and and physical environments. Such a pattern of  reduced epigenetic responsiveness may explain many of the symptoms of both Rett and MECP2 duplication syndrome. As research progresses, the potential role of reduced epigenetic responsiveness may be confirmed or contradicted by new findings.

For more information on epigentics, see:

Schanen, N. C. (2006). Epigenetics of autism spectrum disorders. Hum Mol Genet, 15 Spec No 2, R138-150.

Simmons, D. (2008). Epigenetic influences and disease. Scitable. 1(1): 6.

Weaver, I. C., La Plante, P., Weaver, S., Parent, A., Sharma, S., Diorio, J., et al. (2001). Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Mol Cell Endocrinol, 185(1-2), 205-218.

Weaver, I. C., Szyf, M., & Meaney, M. J. (2002). From maternal care to gene expression: DNA methylation and the maternal programming of stress responses. Endocr Res, 28(4), 699.

Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., Seckl, J. R., et al. (2004). Epigenetic programming by maternal behavior. Nat Neurosci, 7(8), 847-854.
Weaver, I. C., Szyf, M., & Meaney, M. J. (2002). From maternal care to gene expression: DNA methylation and the maternal programming of stress responses. Endocr Res, 28(4), 699.







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