MeCP2 mutations: progress towards understanding and treating Rett syndrome

Abstract

Rett syndrome is a profound neurological disorder caused by mutations in the MECP2 gene, but preclinical research has indicated that it is potentially treatable. Progress towards this goal depends on the development of increasingly relevant model systems and on our improving knowledge of MeCP2 function in the brain.

Fig. 1

Analysis of point mutations responsible for Rett syndrome (RTT) in human and mouse. a The primary protein structure of methyl-CpG-binding protein 2 (MeCP2), which is a chromosomal protein that binds to methylated DNA, highlights two key functional domains—a methyl-CpG-binding domain (MBD) and a NCoR/SMRT co-repressor interaction domain (NID). Shown as red vertical lines below the schematic are the positions of all RTT-causing missense mutations (RettBASE; http://mecp2.chw.edu.au/). The positions of three particular RTT-causing missense mutations—R133C, T158M and R306C, reflecting the spectrum of clinical severity—are indicated above the schematic (modified from [6]). b The approximate clinical severity of patients possessing the specific missense mutations T158M (red), R306C (blue) or R133C (green), based on independent studies using a variety of clinical severity score systems, for example [3]. c Scores of phenotypic severity of mouse models containing the T158M (red), R306C (blue) and R133C (green) missense mutations, in comparison with those of wild-type mice (dark gray solid line) and Mecp2-null mice (pale gray broken line). The asterisks indicate where no animals of that genotype survived beyond the indicated time-point. The data are adapted from Brown et al. [2] and are reproduced with permission of Oxford University Press