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.

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Background: Mutation S151P was found in patients with exercise intolerance.Results: Bacterial analogous substitution (G167P) influences movement of the iron-sulfur protein head domain (ISP-HD), increasing ROS production.Conclusion: This correlation corroborates the recently proposed “semireverse” electron transfer mechanism of ROS production.Significance: The molecular effect identified for S151P may be valid for several other human mutations that affect motion of ISP-HD.