The Rett syndrome (RTT) and the Autism Spectrum Disorder (ASD) are neurodevelopmental disorders which, although presenting different symptoms and evolution, are linked by a common factor: mutations in the same gene, called MECP2. But the answers on how and why the same gene could have a key role in the development of both diseases have just been started to appear.

The RTT is mainly caused by a loss of function of the MECP2 gene, due to mutations that lower or suppress the expression of the resulting protein MeCP2 (more than 95% of RTT patients show this loss of function). On the other hand, the ASD is linked to duplications of the parts of the genome containing the MECP2 gene: in this case, the overexpression of the gene has a part of responsibility in the onset of the disorder.

Behavior of MECP2 gene at the molecular level

These findings have been leading the scientists to study the molecular mechanisms on the basis of the functioning of the MECP2, in order to understand the biochemical pathways shared by RTT and ASD. The protein MeCP2 is found into the cellular nucleus and carries out various regulatory functions (repression of transcription, processing of microRNA, regulation of the RNA splicing). The activity of MeCP2 is also regulated by several modifications in its structure: one of the most important for the brain functions is the SUMOylation.

Molecular details aside, however, it is important to find out about the targets regulated by the MECP2 gene. The most important target is the BDNF gene, whose corresponding protein levels vary according to the activity of the “controller” gene MECP2. Even though the MECP2 regulation is not the only pathway affecting the expression of the BDNF protein, this protein could be considered as a potential biomarker for RTT and ASD.

Brain circuits affected by the MECP2 malfunction

The complex role of MeCP2 protein at the molecular level is reflected in the variety of neuronal circuits that can be affected by its malfunction. For example, MeCP2 may have a role in the stem cells that develop the hippocampus and also is a key component in the homeostatic plasticity (that is, the capacity of neurons to regulate their response to excitatory stimulus). Moreover, MeCP2 regulates the development of various brain circuits, as shown in the following table:

Brain circuitProblems caused by MeCP2 malfunction
GABAergic (GABA, Glutamate)Respiratory problems, shorter life
Aminergic (a- dopaminergic, b- serotonergic)a- Reduction of motor functions

b- Aggressive behavior

Cholinergic (acetylcholine)Anxiety, decreased social activity

Biotechnology, to the rescue

In the last few years, the rapid rise of new gene technologies has allowed the scientists to observe the clinical phenotype of many diseases, including RTT and ASD, in animal models, mainly mice. Biotechnology techniques provide a valid tool to create animals the reproduce the symptoms of the human diseases thanks not only to the insertion or removal of a gene but also to its activation/deactivation in specific moments of the daytime or during the lifespan.

As an example, mice born with the MECP2 gene switched off and developing damaged neuronal circuits, showed a surprising recovery during the adulthood, at the moment of the programmed activation of the MECP2: the animals recovered their motor functions, their synaptic plasticity, and had an increased lifespan. These findings are surprising and very important because they contradict the common thinking that the brain circuits damaged during the childhood cannot improve in the adulthood.

Final considerations

The new genetic strategies promise to be a powerful tool looking at the possibility of future treatments for disorders like RTT and ASD. However, a necessary intermediate step will be the use of transgenic animals closer to our species, such as primates, to test the reliability of such technologies and their safety for our health. Anyway, the genetic manipulation of specific circuits of the brain and the first good results obtained in animal models give us the concrete hope to develop effective methods to help RTT and autistic patient in the future.


Qiu Z. Deciphering MECP2-associated disorders: disrupted circuits and the hope for repair. Curr Opin Neurobiol. 2017 Sep 26;48:30-36

The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).