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Cited by 155Genetics and Neurodevelopmental DisordersEpigenetics and DNA MethylationGenomics and Rare Diseases

Radically truncated MeCP2 rescues Rett syndrome-like neurological defects

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Tillotson, Rebekah, Selfridge, Jim, Koerner, Martha V., Gadalla, Kamal K. E., Guy, Jacky, De Sousa, Dina, Hector, Ralph D., Cobb, Stuart R. +1 more·2017·Nature
DOI 10.1038/nature24058PMC PMC5884422
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Abstract

Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners, including transcriptional co-repressors (for example, the NCoR/SMRT complex), transcriptional activators, RNA, chromatin remodellers, microRNA-processing proteins and splicing factors. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons. At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain and the NCoR/SMRT interaction domain. Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.

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Research works printed but not linked: 35

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Cited by

Sorted by citations

Authors
Tillotson, R., Selfridge, J., Koerner, M. V., Gadalla, K. K. E., Guy, J., De Sousa, D., Hector, R. D., Cobb, S. R., & Bird, A.
Affiliations
  • Wellcome Centre for Cell Biology (GB)
  • Tanta University (EG)
  • University of Glasgow (GB)
Corresponding author
Bird, Adrian
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2017-10
Volume
550
Issue
7676
Pages
398-401
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature24058
PMC
PMC5884422
OpenAlex
W2762557409
Cited by
155
References
3
Citations by year
2026: 14 · 2025: 8 · 2024: 22 · 2023: 14 · 2022: 16 · 2021: 25 · 2020: 19 · 2019: 16 · 2018: 18 · 2017: 3
FWCI
10.17
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • Wellcome Trust (107930/Z/15/Z)
  • Biotechnology and Biological Sciences Research Council (BB/J01446X/1, 1272176)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
MeCP2, Rett syndrome, MECP2 mutations, methyl-CpG binding domain, gene therapy, viral gene delivery, epigenetic regulation, DNA methylation, X-linked disorders, protein truncation, epigenetic reader protein
MeSH terms
Protein Domains, Animals, Brain, DNA, Genetic Complementation Test, HeLa Cells, Humans, Male, Phenotype, Transduction, Genetic, Genetic Therapy, Rett Syndrome, 3T3 Cells, Sequence Deletion, Mutation, Missense, Mice, Methyl-CpG-Binding Protein 2, Protein Stability

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