Title | Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Lyst MJ, Ekiert R, Ebert DH, Merusi C, Nowak J, Selfridge J, Guy J, Kastan NR, Robinson ND, Alves Fde Lima, Rappsilber J, Greenberg ME, Bird A |
Journal | Nat Neurosci |
Volume | 16 |
Issue | 7 |
Pagination | 898-902 |
Date Published | 2013 Jul |
ISSN | 1546-1726 |
Keywords | Animals, Brain, Cells, Cultured, Disease Models, Animal, Exploratory Behavior, Green Fluorescent Proteins, Histone Deacetylases, Immunoprecipitation, Methyl-CpG-Binding Protein 2, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Molecular, Mutation, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2, Rett Syndrome |
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. |
DOI | 10.1038/nn.3434 |
Alternate Journal | Nat. Neurosci. |
PubMed ID | 23770565 |
PubMed Central ID | PMC3786392 |
Grant List | K08MH90306 / MH / NIMH NIH HHS / United States 084229 / / Wellcome Trust / United Kingdom 091580 / / Wellcome Trust / United Kingdom P30 HD018655 / HD / NICHD NIH HHS / United States K08 MH090306 / MH / NIMH NIH HHS / United States 092076 / / Wellcome Trust / United Kingdom R01 NS048276 / NS / NINDS NIH HHS / United States R01NS048276 / NS / NINDS NIH HHS / United States 091020 / / Wellcome Trust / United Kingdom P30-HD 18655 / HD / NICHD NIH HHS / United States |
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