The X-chromosomal MECP2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. MECP2 is mutated in Rett syndrome. This paper found that that mice with ~50% transgenic overexpression of Mecp2 have enhanced aggressive behavior. When the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, the authors performed a phenotype-based genetic association study in schizophrenic individuals and found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3’UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. MECP2 mRNA expression in peripheral blood mononuclear cells was also affected by ~50% (rs2734647: C > T). Finally, the authors showed that the brain-expressed, species-conserved miR-511 binds to MECP2 3′ UTR only in T carriers, thereby suppressing gene expression. In conclusion, this study provides mouse data supporting an interaction between genetic background and mild Mecp2 overexpression and human data that link a genetic variation to MECP2 expression and behavior.
Posted by Nicola Brunetti-Pierri, MD, FACMG