Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2), which encodes the MeCP2 protein. RTT is a MECP2-related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2. Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2-related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype-phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.

Keywords: DNA methylation; disease modeling; epigenetics; neurodevelopmental disorders; therapeutics.

Figure 1

Disease stages in Rett syndrome. The progression of Rett syndrome can be described in four stages of disease. In Stage 1 (early onset), children develop mostly typically with possible developmental delay. In Stage 2 (regression), children undergo developmental regression over the course of weeks, months, or years with loss of previously acquired skills including purposeful hand movements and spoken language. Children also begin to develop breathing and gait abnormalities during this period. In Stage 3 (plateau), children usually experience stabilization of cognitive abilities and have onset of other medical conditions such as seizures. In Stage 4 (late motor deterioration) individuals with RTT experience decreasing mobility and may develop parkinsonian features.

Figure 2

Schematic of MeCP2 functional domains. Schematic illustration of MeCP2 protein from the N-terminus (right) to C-terminus (left). The two main protein domains are indicated in shades of green: methyl-binding domain (MBD) and transcription repression domain (TRD). The location of the NCoR/SMRT interaction domain (NID) within the TRD is indicated in black. The intervening domain (ID) between the MBD and TRD is also indicated in black.

Figure 3

Common MECP2 mutations in Rett syndrome. Frequency map of MECP2 mutations identified in girls with RTT from the NIH Natural History Study of Rett Syndrome and Related Disorders. Mutation frequency is depicted on the y-axis while the start of the mutation along the protein sequence is indicated on the x-axis. A schematic of the MeCP2 protein domains is provided for reference. The 8 common point mutations and set of C-terminal mutations are indicated.