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Rett syndrome: a complex disorder with simple roots

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.

Abstract

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.

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Figure 1: The primary structure of MeCP2 illustrating domains implicated in the pathology of Rett syndrome.
Figure 2: Summary of proposed molecular functions for MeCP2.
Figure 3: Two models of MeCP2 function are consistent with the mutation spectrum of Rett syndrome.

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Acknowledgements

The authors thank R. Tillotson for critical reading of the manuscript and W. Borek for help with the figures. They are grateful to all members of A.B.'s laboratory for discussions. Work in the laboratory of A.B. is funded by The Wellcome Trust (grants 091580 and 092076) and the Rett Syndrome Research Trust.

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Glossary

AT-hook

A DNA-binding motif first identified in the high-mobility group (HMG) chromatin proteins. It specifically recognizes the minor groove of AT-rich DNA.

SIM1-expressing neurons

Neurons expressing the transcription factor SIM1 (single-minded homologue 1) found in tissues such as the hypothalamus, which is involved in regulating body weight homeostasis.

GABA-releasing neurons

Neurons that produce γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain.

CpG dinucleotides

Cytosine bases connected to adjacent guanine bases in the same strand of DNA. This sequence is symmetrical and is therefore base-paired with CpG on the complementary DNA strand.

Imprinted genes

Genes that are expressed in a parent-of-origin-specific manner. They frequently show DNA methylation specific to the parent of origin.

Matrix attachment regions

AT-rich DNA elements defined by their ability to interact with the nuclear matrix in vitro. They are thought to organize chromatin into a series of loops or domains.

Chromocentres

Aggregations of heterochromatin in mouse nuclei that stain readily with DAPI (4′,6-diamidino-2-phenylindole). These regions are enriched in major satellite repeat elements.

Nucleosomal arrays

Arrays that can be assembled in vitro by reconstituting recombinant histones with DNA. They represent a useful tool to study the effect of other proteins on chromatin structure.

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Lyst, M., Bird, A. Rett syndrome: a complex disorder with simple roots. Nat Rev Genet 16, 261–275 (2015). https://doi.org/10.1038/nrg3897

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