title: Ube3a/E6AP is involved in a subset of MeCP2 functions.
abstract: Rett syndrome (RTT) and Angelman syndrome (AS) are devastating neurological disorders that share many clinical features. The disease-causing mutations have been identified for both syndromes. Mutations in Methyl-CpG Binding Protein 2 (MECP2) are found in a majority of patients with classical RTT while absence of maternal allele or intragenic mutation in the maternal copy of UBE3A gene encoding the human papilloma virus E6-associated protein (E6AP) cause most cases of AS. Extensive studies have been performed to determine the cause of the neurological problems in each disease. However, the genetic and molecular basis of the overlap in phenotypes between RTT and AS remains largely unknown. Here we present evidence that the phenotypic similarities between the two syndromes might be due to the shared molecular functions between MeCP2 and E6AP in gene expression. Our genetic and biochemical studies suggest that E6AP acts as an essential cofactor for a subset of MeCP2 functions. Specifically, decreased expression of Ube3a was able to rescue the cellular phenotypes induced by MECP2-overexpression in Drosophila. And biochemical assays using mice and cell culture systems show that MeCP2 and E6AP physically interact and regulate the expression of shared target genes. Together these data suggest that MeCP2 and E6AP play a role in the transcriptional control of common target gene expression and provide some insight into why RTT and AS share several neurological phenotypes.
authors.affiliation: Department of Genetics, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Soeun
authors.initials: S
authors.lastname: Kim
authors.forename: Maria
authors.initials: M
authors.lastname: Chahrour
authors.forename: Shay
authors.initials: S
authors.lastname: Ben-Shachar
authors.forename: Janghoo
authors.initials: J
authors.lastname: Lim
mesh_terms: D000818:Animals; D056970:Co-Repressor Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism / Q000648:ultrastructure; D005123:Eye / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D029721:Drosophila Proteins; D051783:Methyl-CpG-Binding Protein 2; C532444:Ube3a protein, Drosophila; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Angelman syndrome; MeCP2; Rett syndrome; Ube3a/E6AP