Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr(286) and Thr(305/306), resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients.
Pubmed ID: 22174738 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on March 17, 2022. A large-scale database of genetics and genomics data associated to a web-interface and a set of methods and algorithms that can be used for mining the data in it. The database contains two categories of single nucleotide polymorphism (SNP) annotations: # Physical-based annotation where SNPs are categorized according to their position relative to genes (intronic, inter-genic, etc.) and according to linkage disequilibrium (LD) patterns (an inter-genic SNP can be annotated to a gene if it is in LD with variation in the gene). # Functional annotation where SNPs are classified according to their effects on expression levels, i.e. whether they are expression quantitative trait loci (eQTLs) for that gene. SCAN can be utilized in several ways including: (i) queries of the SNP and gene databases; (ii) analysis using the attached tools and algorithms; (iii) downloading files with SNP annotation for various GWA platforms. . eQTL files and reported GWAS from NHGRI may be downloaded.
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