MeCP2 mutations: progress towards understanding and treating Rett syndrome

Shah and Bird Genome Medicine (2017) 9:17 DOI 10.1186/s13073-017-0411-7 COMMENT Open Access MeCP2 mutations: progress towards understanding and treating Rett syndrome Ruth R. Shah and Adrian P. Bird* Editorial summary 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. Rett syndrome genetics It is now 50 years since Andreas Rett reported his observations on 22 girls with similar clinical features, subsequently known as Rett syndrome (RTT). Classic RTT is defined by a regression phase and subsequent stabilization of diagnostic criteria, which include partial or complete loss of spoken language, dyspraxic gait and stereotypic hand movements such as ‘hand mouthing’ [1]. With very few familial cases available, it took a further 33 years before mutations affecting a protein called methyl-CpG-binding protein 2 (MeCP2) were shown to be the almost exclusive cause of this neurological disorder. The MECP2 gene is located on the X chromosome, and RTT is classified as an X-linked dominant disorder. Thus, as expected, males are more severely affected and rarely survive infancy. Rett syndrome therefore overwhelmingly affects females, who, owing to X chromosome inactivation, have a mixture of cells that express either the wild-type or mutant version of MeCP2. This cellular mosaicism defines RTT and highlights the importance of MeCP2 for proper neuronal function. In the light of new insights into the function of MeCP2 and the novel gene therapy technologies currently being developed, here we discuss recent progress in understanding the molecular pathogenesis of this complex disease and the search for a therapy. * Correspondence: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Max Born Crescent, Edinburgh EH16 5DS, UK Model systems for studying Rett syndrome Mouse models are a vital tool for studying RTT as MeCP2 deficiency closely mimics the clinical features of the human disorder, including motor defects and breathing arrhythmia. Indeed, a recent study [2] of animals expressing three Mecp2 mutations with differing average clinical severity showed a matching severity spectrum in the mice (Fig. 1) [3]. These findings reflect the high conservation of the MeCP2 amino acid sequence between human and mouse (95% identical) and the parallel dynamics of MeCP2 expression during brain development. Thus, despite differences in the brain structure and developmental timing between human and mouse, these striking similarities suggest that the molecular consequences of MeCP2 mutation are similar between the two species. Early indications that RTT results exclusively from absence of MeCP2 in the brain have recently been reinforced by a mouse model that has normal levels of central nervous system MeCP2, but lacks this protein in the rest of the body, and shows none of the major phenotypes associated with RTT-like mice [4]. Advances in cellular technologies have allowed further development of human tissue-culture models of RTT [5, 6]. The ability to study a homogeneous population of human neurons eliminates the complexity of the brain, allows more precise genetic manipulation and simplifies the interpretation of findings [5]. It also streamlines screening of potential therapeutics and viral delivery vectors in a human neuronal setting. In addition to mice, a Mecp2-null rat model has been produced (Sage Labs), and there has been progress towards generating non-human primate models of RTT [7] that should be beneficial for testing once further phenotypic characterization is available. MeCP2—a genome-wide transcriptional repressor Progress in understanding the molecular aetiology of RTT has been facilitated by combining data from clinical genetics and mouse models with cellular and biochemical investigations. Importantly, nearly all RTT missense © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shah and Bird Genome Medicine (2017) 9:17 a Page 2 of 4 R133C T158M R306C 1 486 MBD b NID RTT patient severity schematic c Mouse phenotypic scores T158M R306C R133C Phenotypic severity score Approximate clinical severity 10 * * 8 6 * 4 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Age (weeks) R133C RTT mutations R306C WT T158M Null Fig. 1 Analysis of point mutations responsible for Rett syndrome (RTT) in human and mouse. a The primary protein structure of methyl-CpGbinding protein 2 (MeCP2), which is a chromosomal protein that binds to methylated DNA, highlights two key functional domains—a methylCpG-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 mutations cluster in two discrete domains of MeCP2: the methyl-CpG-binding domain (MBD) and the NCoR/ SMRT co-repressor interaction domain (NID) (Fig. 1) [6]. With a crystal structure of the MBD bound to methylated DNA available, we can understand the loss of DNA binding caused by RTT mutations in the MBD (reviewed in [6]). Likewise, most amino acids in the NID—which interact with NCoR/SMRT co-repressor complexes—when mutated cause RTT syndrome, and all NID mutations tested so far prevent the interaction with this large multi-component complex. The NCoR/SMRT complex includes the transcriptional-repre (...truncated)