Angelman syndrome (AS) is a genetic disorder that affects the nervous system affecting 1 in 12,000 individuals. Features of AS include developmental delay, speech impairment, seizures, microcephaly, and ataxia. AS individuals have deletion of the maternal copy 15q11.2–15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the gene UBE3A and it has been shown that deregulation of E6AP gives rise to AS. It has been shown that E6AP also acts as a coactivator of the estrogen receptor (ER). Until now, all  published studies have examined the role of the ubiquitin-protein ligase activity of E6AP in the development of AS, and it is not known what role the newly discovered coactivation functions of E6AP and ER plays in the pathology of AS. Here, this study identified a novel E6AP and ER direct regulation of a gene NPY1R known to be involved in learning and memory processes. This regulation involves recruitment of E6AP and ER to a newly discovered functional estrogen response element (ERE) located at the NPY1R gene promoter leading to an increase of transcription of the NPY1R gene in neurons upon estrogen treatment. In fact, the loss of E6AP leads to a 31% decrease in NPY1R expression. The data presented proves that the transcriptional coactivation function of E6AP may have a crucial role in the pathobiology of AS. This function reveals the possibility of using novel treatment modalities for reversing neurological manifestations in AS.

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