The Molecular Functions of MeCP2 in Rett Syndrome Pathology.

Osman Sharifi,Dag H Yasui

doi:10.3389/fgene.2021.624290

Abstract

MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.

Highlights

MeCP2 research efforts have been extensive and have greatly advanced the fields of epigenetics, neuroscience and chromatin research
Patients with mutations in CDKL5 were considered to have a severe variant of Rett, this was later categorized as a separate disease (Fehr et al, 2013)
As these rare FOXG1 mutation patients present with disease from birth and have other symptoms that do not overlap with Rett, a proposal to classify these patients as a separate syndrome was recently submitted (Cutri-French et al, 2020)

Summary

INTRODUCTION

MeCP2 research efforts have been extensive and have greatly advanced the fields of epigenetics, neuroscience and chromatin research. In a similar study it was found that long range interactions between the Prader-Willi imprinting center (PWS-IC) and CHRNA7 modulated gene expression in neurons (Yasui et al, 2011) These studies in cell lines were consistent with in vitro studies from the Hansen lab revealing that MeCP2 was able to interact with DNA outside of the MBD domain, thereby accounting for the ability of one MeCP2 molecule to bind to two sites simultaneously in chromatin looping (Nikitina et al, 2007). Perhaps the most compelling evidence that MeCP2e1 has an essential function that differs from MeCP2e2 is the finding that MeCP2e1 is the evolutionarily older isoform, as orthologs have been identified in vertebrates back to bony fish (Osteichthyes) and amphibians (Mnatzakanian et al, 2004)

Glial Cells Are Critical for Rett Syndrome Pathology

Findings

DISCUSSION