- Over 300 different mutations, causing loss of function and mainly affecting the parental allele
- MeCP2 can both activate and repress gene expression
- Due to X-inactivation, *MECP2* expression is mosaic at the tissue level - with generally a 50/50 ratio of wild-type and mutated *MECP2* gene
- The *MECP2* gene has 4 exons that encode 2 isoforms: the longer and more abundant MeCP2α and the shorter MeCP2ꞵ. Both isoforms bind to methylated CpG dinucleotide sequences on chromosomes via the methyl-CpG-binding domain. The transcriptional repressor site recruits histone deacetylases that induce chromatin compaction - stopping transcription from occurring. 

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- Neuroanatomical abnormalities
- Mutation in MECP2 protein
- High expression of MeCP2 in the brain
- Other gene targets associated with Rett Syndrome

Neurobiology of Rett Syndrome

Sontheimer, H. (2015). Diseases of the Nervous System. Academic Press. 

Diseases of the Nervous System 

- Decreased brain volume due to lack of postnatal growth - seen especially in the frontal and prefrontal cortices
- Smaller, more densely packed cortical neurons with simpler dendrites and immature dendritic spines
- Decreased pigmentation in the substantia nigra, suggesting a decrease in dopamine in the brain
- Abnormalities seen in basically all neurotransmitter systems, with decreased acetylcholine being the most common 


Neuroanatomical Differences in Rett Syndrome

Mutation in MECP2 Protein in Rett Syndrome

MeCP2 has high expression in the neurons and glia of the brain, with a particular increase in expression during postnatal development
- BDNF (which is important for synapse development and plays an important role in learning and memory) is always repressed by MeCP2 binding to one of its promoters. Loss of MeCP2 impairs activity-dependent release of BDNF and deletion of *BDNF* gene has the same symptoms as *MECP2* deletion in mice.

High Expression of MeCP2 in the Brains of Persons with Rett Syndrome

- *DXL5* (neuronal transcription factor)
- Serum glucocorticoid-inducible kinase 1 (*Sgk1*)
- *UBE3A* (ubiquitin ligase)
- Corticotropin-releasing hormone (*CRH*) - which may explain why there are anxiety-related symptoms 


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