Journal Article

Rett syndrome: a complex disorder with simple roots

Lyst, Matthew J., Bird, Adrian

2015

Overview

Key Points Methyl-CpG-binding protein 2 (MeCP2) functions throughout the brain. Inactivation of MeCP2 in various brain regions and neuronal subtypes has defined the role of MeCP2 in these areas. MeCP2 is a protein that associates with chromatin. The methyl-CpG-binding domain (MBD) is the primary determinant of DNA binding by MeCP2, but other DNA-binding modules are also reported in the molecule. There is evidence that MeCP2 can positively and negatively regulate gene expression at transcriptional and post-transcriptional levels. Mutations in patients with Rett syndrome (RTT) highlight critical regions of MeCP2 (the MBD, an AT-hook and the NCOR–SMRT interaction domain (NID) that determine the presence and severity of RTT pathology. Different models of MeCP2 function (chromatin compaction or recruitment of nuclear receptor co-repressor (NCOR)–SMRT (silencing mediator of retinoic acid and thyroid hormone receptor)) might be consistent with the RTT mutation spectrum. Rett syndrome is a neurological disorder associated with mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). This Review details emerging insights into the link between the functions of MeCP2 and the pathogenesis of Rett syndrome. Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked gene MECP2 (methyl-CpG-binding protein 2). Two decades of research have fostered the view that MeCP2 is a multifunctional chromatin protein that integrates diverse aspects of neuronal biology. More recently, studies have focused on specific RTT-associated mutations within the protein. This work has yielded molecular insights into the critical functions of MeCP2 that promise to simplify our understanding of RTT pathology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/45/612/1229 / 692/420 / Agriculture / Animal Genetics and Genomics / Animals / Biomedicine / Brain - pathology / Brain - physiopathology / Cancer Research / Development and progression / Disease Models, Animal / DNA - chemistry / DNA - metabolism / Gene expression / Gene Expression Regulation / Gene Function / Gene mutations / Genetic aspects / Health aspects / Human Genetics / Humans / Methyl-CpG-Binding Protein 2 - genetics / Methyl-CpG-Binding Protein 2 - physiology / Mice / Mice, Knockout / Models, Neurological / Mutation / Neurons - pathology / Neurons - physiology / Protein Binding / Rett syndrome / Rett Syndrome - genetics / Rett Syndrome - pathology / Rett Syndrome - physiopathology / review-article / Trans-Activators - genetics / Trans-Activators - physiology