Rett Syndrome and MeCP2

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.

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

“…2, namely 1) MECP2 influences global translation by enhancing the AKT/mTOR signaling pathway [46], 2) Alternative splicing of downstream gene products is affected because MECP2 forms a complex with YB1, an important splicing factor [29, 47–51], 3) Expression of various microRNAs and long non-coding RNAs is regulated by MECP2 (20, 45, 47–49), and 4) MECP2 triggers the chromatin compaction at methylated DNA sites which regulates the transcription of adjacent genes (34, 37–41). The last one is an important (and best investigated) pathway and will be explained in detail below.…”

Epigenetic mechanisms: A possible link between autism spectrum disorders and fetal alcohol spectrum disorders

“…Interestingly, MeCP2 deficiency, observed in Rett syndrome, is linked to reduced spine densities in area CA1 of the hippocampus [154] similar to those in FASD [155,156]. Additionally, Liyanage & Rastegar (2014) report that MECP2 mutations or altered expression are associated with a spectrum of neurodevelopmental disorders such as ASDs with recent links to FASDs [157].…”

Bioinformatic Analysis of DNA Methylation in Neural Progenitor Cell Models of Alcohol Abuse

“…Ethanol-induced alterations of methylation can contribute to deregulating MeCP2 expression (Liyanage, Rastegar 2014). Previous work from this group found MeCP2 expression changes following DNA methylation at adjacent regulatory elements using murine embryonic-derived NSCs, which previously had been shown to express MeCP2 and were used as a model for neural development.…”