Abstract
Rett syndrome (RTT) is a severe neurological disorder that is caused by mutations in the MECP2 gene. Many missense mutations causing RTT are clustered in the DNA-binding domain of MeCP2, suggesting that association with chromatin is critical for its function. We identified a second mutational cluster in a previously uncharacterized region of MeCP2. We found that RTT mutations in this region abolished the interaction between MeCP2 and the NCoR/SMRT co-repressor complexes. Mice bearing a common missense RTT mutation in this domain exhibited severe RTT-like phenotypes. Our data are compatible with the hypothesis that brain dysfunction in RTT is caused by a loss of the MeCP2 'bridge' between the NCoR/SMRT co-repressors and chromatin.
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Acknowledgements
We thank Harrison Gabel for advice and materials, and Martha Koerner, Thomas Clouaire and Sabine Lagger for comments on the manuscript. The work was supported by a grant to A.B. and M.E.G. from the Rett Syndrome Research Trust and by grants from the Wellcome Trust (to A.B.) and the NIH R01NS048276 (to M.E.G.). D.H.E. was supported by NIH grant K08MH90306. The Mouse Gene Manipulation Facility of the Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (IDDRC) was supported by grant NIHP30-HD 18655. R.E. and J.N. were funded by Wellcome Trust 4 year PhD studentships and J.R. holds a Wellcome Trust Senior Fellowship.
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M.J.L. carried out protein purification for mass spectrometry, deletion analysis and mutation analysis. R.E. performed protein purification for mass spectrometry and repression assays. C.M. produced Mecp2R306C-EGFP knock-in ES cells, performed neuronal differentiation and immunofluorescence analysis. J.N. performed in vitro protein binding assays. J.G. and J.S. produced Mecp2-EGFP knock-in mice and Mecp2T158M-EGFP ES cells. F.d.L.A. and J.R. performed mass spectrometry analysis. D.H.E., N.R.K., N.D.R. and M.E.G. generated and phenotyped Mecp2R306C knock-in mice. M.J.L., R.E. and A.B. wrote the manuscript.
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Lyst, M., Ekiert, R., Ebert, D. et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci 16, 898–902 (2013). https://doi.org/10.1038/nn.3434
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DOI: https://doi.org/10.1038/nn.3434
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