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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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Brain / pathology
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Cells, Cultured
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Disease Models, Animal
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Exploratory Behavior / physiology
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Green Fluorescent Proteins / genetics
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Immunoprecipitation
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Methyl-CpG-Binding Protein 2 / genetics*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Molecular
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Mutation / genetics*
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Nuclear Receptor Co-Repressor 1 / genetics
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Nuclear Receptor Co-Repressor 1 / metabolism*
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Nuclear Receptor Co-Repressor 2 / genetics
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Nuclear Receptor Co-Repressor 2 / metabolism*
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Rett Syndrome / genetics*
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Rett Syndrome / pathology
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Rett Syndrome / physiopathology
Substances
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Methyl-CpG-Binding Protein 2
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Ncor1 protein, mouse
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Histone Deacetylases
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histone deacetylase 3