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Autism is a common neurodevelopmental disorder of complex genetic etiology. Rett syndrome, an X-linked dominant disorder caused by MECP2 mutations, and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. MECP2 encodes methyl-CpG-binding protein 2 that acts as a transcriptional repressor for methylated gene constructs but is surprisingly not required for maintaining imprinted gene expression. Here, we test the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods were used including automated quantitation of immunofluorescence and in situ hybridization by laser scanning cytometry on tissue microarrays, immunoblot and TaqMan PCR. The results demonstrated significant defects in UBE3A/E6AP expression in two different Mecp2 deficient mouse strains and human Rett, Angelman and autism brains compared with controls. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. A non-imprinted gene from 15q11-q13, GABRB3, encoding the beta3 subunit of the GABAA receptor, also showed significantly reduced expression in multiple Rett, Angelman and autism brain samples, and Mecp2 deficient mice by quantitative immunoblot. These results suggest an overlapping pathway of gene dysregulation within 15q11-q13 in Rett, Angelman and autism and implicate MeCP2 in the regulation of UBE3A and GABRB3 expressions in the postnatal mammalian brain.

Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3