Review Article

Rett syndrome: insights into genetic, molecular and circuit mechanisms

  • Nature Reviews Neurosciencevolume 19pages368382 (2018)
  • doi:10.1038/s41583-018-0006-3
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Abstract

Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into RTT have greatly advanced our understanding of the function and regulation of the multifunctional protein MeCP2. Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms. These factors present challenges to the search for mechanism-based therapeutics for RTT and suggest specific approaches that may be more effective than others.

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Acknowledgements

The authors thank H. Tsang for thoughtful discussions and critical reading of the manuscript. The authors apologize to colleagues whose research was not cited owing to the broad scope and space limitations of this Review. The authors’ research is supported by a Human Frontier Science Program Long-Term Fellowship (J.P.K.I.) and by US National Institutes of Health grants MH085802 and EY007023, and the Simons Foundation Autism Research Initiative through the Simons Center for the Social Brain (M.S.).

Reviewer information

Nature Reviews Neuroscience thanks T. Pizzorusso and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Affiliations

  1. Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Jacque P. K. Ip
    •  & Mriganka Sur
  2. Department of Neurosciences, School of Medicine, The University of New Mexico, Albuquerque, NM, USA

    • Nikolaos Mellios

Authors

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Contributions

J.P.K.I., N.M. and M.S. researched data for the article, contributed substantially to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Mriganka Sur.

Glossary

Classic RTT

The most common form of RTT. Several atypical forms of RTT have been described. The classic and atypical forms may differ by their symptoms or by the specific gene mutation.

Random X chromosome inactivation

Random inactivation of one X chromosome in early embryonic cells in females.

Somatic mosaics

The presence of two populations of cells with different genotypes (mutation-positive and mutation-negative) in one individual.

Hypotonia

A state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often resulting in muscle weakness.

Guide RNA

A short synthetic RNA composed of a 20-nucleotide sequence, homologous to the gene of interest, and a Cas9 nuclease-recruiting sequence for CRISPR–Cas9 gene editing.

Epigenetic reader

A protein that reads specific epigenetic marks on DNA.

Long genes

Genes with length greater than 100 kb.

Gene bodies

Regions of DNA from the transcription start site to the end of the transcript.

Transcription start sites

The location where transcription starts at the 5´ end of a gene sequence. Promoters are located near the transcription start sites of genes.

AT hooks

DNA-binding motifs that bind specifically to AT-rich DNA.

Chromatin loops

When stretches of genomic sequence in the same chromosome are physically closer together than to the intervening sequences. These are involved in regulating chromatin organization and gene expression.

Primary miRNAs

(pri-miRNAs). Large primary precursor, hairpin-structured, microRNA transcripts that are subsequently cleaved to generate intermediate precursor microRNAs and mature microRNAs.

Stereotypies

Diagnostic repetitive behaviours. Patients with RTT develop repetitive hand movements, a diagnostic criterion for RTT. Mouse models of RTT also develop repetitive behaviour.

Fragile X syndrome

A genetic disorder, caused by mutations in the FMR1 gene, that includes developmental problems such as learning disabilities and cognitive impairment.

Reversal potential

The membrane potential at which a given ion has no net current flow through the cell membrane.

Retinogeniculate synapses

Synaptic connections projecting directly from retinal ganglion cells in the retina to the neurons in the lateral geniculate nucleus.