title: Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor.
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.
authors.affiliation: The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lyst
authors.forename: Robert
authors.initials: R
authors.lastname: Ekiert
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Ebert
authors.forename: Cara
authors.initials: C
authors.lastname: Merusi
authors.forename: Jakub
authors.initials: J
authors.lastname: Nowak
authors.forename: Jim
authors.initials: J
authors.lastname: Selfridge
authors.forename: Jacky
authors.initials: J
authors.lastname: Guy
authors.forename: Nathaniel R
authors.initials: NR
authors.lastname: Kastan
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Robinson
authors.forename: Flavia
authors.initials: F
authors.lastname: de Lima Alves
authors.forename: Juri
authors.initials: J
authors.lastname: Rappsilber
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000099186:Histone Deacetylase 3
chemical_list: D049452:Green Fluorescent Proteins; D006655:Histone Deacetylases; D051783:Methyl-CpG-Binding Protein 2; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D000099186:Histone Deacetylase 3; C539128:Ncor1 protein, mouse; C485184:enhanced green fluorescent protein