Abstract
Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.
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Abbreviations
- 5hmC:
-
5-Hydroxymethylcytosine
- 5mC:
-
5-Methylcytosine
- ALC:
-
Acetyl-l-carnitine
- ASD:
-
Autism spectrum disorders
- BDNF:
-
Brain-derived neurotrophic factor
- CREB:
-
cAMP response element-binding protein
- CTD:
-
C-terminal domain
- DNMT:
-
DNA methyltransferases
- E:
-
Enhancer
- EE:
-
Environmental enrichment
- ENCODE:
-
Encyclopaedia of DNA elements
- FASD:
-
Fetal alcohol spectrum disorders
- GA:
-
Glatiramer acetate
- HDAC:
-
Histone deacetylases
- HMGN1:
-
High mobility group N1 protein
- HP1:
-
Heterochromatin binding protein 1
- ID:
-
Inter-domain
- IGF1:
-
Insulin-like growth factor 1
- iPSC:
-
Induced pluripotent stem cells
- IRAK1:
-
Interleukin-1 receptor associated kinase gene
- lncRNA:
-
Long noncoding RNAs
- MBD:
-
Methyl binding domain
- MeCP2:
-
Methyl CpG binding protein 2
- MeP:
-
Mecp2 promoter
- miRNAs:
-
MicroRNAs
- mnt:
-
Months
- MRE:
-
miRNA response elements
- NG:
-
Nodose cranial sensory ganglial cells
- NSCs:
-
Neural stem cells
- NTD:
-
N-terminal domain
- PTMs:
-
Posttranslational modifications
- RCP:
-
Red opsin gene
- RTT:
-
Rett syndrome
- S:
-
Silencer
- TM:
-
Tamoxifen
- TRD:
-
Transcription repression domain
- TSA:
-
Trichostatin A
- wks:
-
Weeks
- yr:
-
Years
- ω-3 PUFAs:
-
ω-3 polyunsaturated fatty acids
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Acknowledgments
We apologize that due to space limitations, many excellent papers could not be included in this review. We thank all members of the Rastegar laboratory for helpful discussions. The research in the Rastegar Laboratory is supported by funds from Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant 372405-2009), Canadian Institute of Health Research (CIHR Team Grant TEC-128094, and CIHR Catalyst Grant CEN-132383), The Health Sciences Centre Foundation (HSCF), Scottish Rite Charitable Foundation of Canada (SRCFC, Grant 10110), and Graduate Enhancement of Tri-council Stipend (GETS). VRBL is a recipient of MHRC/UMGF studentship award.
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Liyanage, V.R.B., Rastegar, M. Rett Syndrome and MeCP2. Neuromol Med 16, 231–264 (2014). https://doi.org/10.1007/s12017-014-8295-9
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DOI: https://doi.org/10.1007/s12017-014-8295-9