Journal Article

Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor

Merusi, Cara, Selfridge, Jim, Rappsilber, Juri, Nowak, Jakub, Robinson, Nathaniel D, Lyst, Matthew J, de Lima Alves, Flavia, Ekiert, Robert, Bird, Adrian, Greenberg, Michael E, Ebert, Daniel H, Guy, Jacky, Kastan, Nathaniel R

2013

Overview

In this study, the authors show that MeCP2 interacts with the NCoR/SMRT co-repressor complex and that a discrete cluster of Rett syndrome–causing mutations in the C-terminal domain of MeCP2 disrupts this interaction, impairing transcriptional repression. Knock-in mice expressing one of these MeCP2 missense mutations exhibit severe motor phenotypes. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/200 / 631/378/1689/1373 / 631/378/340 / Amino acids / Animal Genetics and Genomics / Animals / Antibodies / Behavioral Sciences / Binding proteins / Biological Techniques / Biomedicine / Brain / Brain - metabolism / Brain - pathology / Cells, Cultured / Chromatin / Disease Models, Animal / DNA methylation / Exploratory Behavior - physiology / Genetic aspects / Green Fluorescent Proteins - genetics / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Immunoprecipitation / Methyl-CpG-Binding Protein 2 - genetics / Mice / Mice, Inbred C57BL / Mice, Transgenic / Models, Molecular / Mutation / Mutation - genetics / Neurobiology / Neurosciences / Nuclear Receptor Co-Repressor 1 - genetics / Nuclear Receptor Co-Repressor 1 - metabolism / Nuclear Receptor Co-Repressor 2 - genetics / Nuclear Receptor Co-Repressor 2 - metabolism / Peptides / Properties / Proteins / Repressor proteins / Rett syndrome / Rett Syndrome - genetics / Rett Syndrome - pathology / Rett Syndrome - physiopathology