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: Matthew J Lyst, Robert Ekiert, Daniel H Ebert, Cara Merusi, Jakub Nowak, Jim Selfridge, Jacky Guy, Nathaniel R Kastan, Nathaniel D Robinson, Flavia de Lima Alves, Juri Rappsilber, Michael E Greenberg, Adrian Bird
• Journal: Nature neuroscience (Nat Neurosci) Vol. 16 Issue 7 Pg. 898-902 (Jul 2013) ISSN: 1546-1726 [Electronic] United States
• PMID: 23770565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Methyl-CpG-Binding Protein 2
• Ncor1 protein, mouse
• Nuclear Receptor Co-Repressor 1
• Nuclear Receptor Co-Repressor 2
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• Histone Deacetylases
• histone deacetylase 3

Topics

• Animals
• Brain (metabolism, pathology)
• Cells, Cultured
• Disease Models, Animal
• Exploratory Behavior (physiology)
• Green Fluorescent Proteins (genetics)
• Histone Deacetylases (genetics, metabolism)
• Immunoprecipitation
• Methyl-CpG-Binding Protein 2 (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Molecular
• Mutation (genetics)
• Nuclear Receptor Co-Repressor 1 (genetics, metabolism)
• Nuclear Receptor Co-Repressor 2 (genetics, metabolism)
• Rett Syndrome (genetics, pathology, physiopathology)