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UBE3A and the Angelman Syndrome 

UBE3A and the Angelman Syndrome
UBE3A and the Angelman Syndrome

Charles A. Williams

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date: 24 February 2021

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of the ubiquitin-protein ligase, UBE3A, in the brain. UBE3A shows parent-specific differential expression, or imprinting, limited to brain and spinal cord neurons (glial cells are not imprinted). In non-CNS tissues, the maternal and paternal alleles of UBE3A are biallelically expressed. AS results from several genetic mechanisms that disrupt the functional allele of UBE3A inherited from the mother; absence of a functional paternal allele of UBE3A causes no phenotypic effects. Clinical features involve the combination of severe intellectual deficiency, seizures, absent speech, hypermotoric and ataxic movements, happy demeanor and hypermotoric behaviors. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent specific DNA methylation imprints in the critical 15q11.2-q13 genomic region identifies 75 to 80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and those with paternal uniparental disomy (UPD). The landscape of UBE3A cellular effects is immense as the protein has multiple targets and protein associations. Some of these effects are directly related to its established role in ubiquitination of proteins targeted for proteasome degradation but additional effects may involve other types of protein regulation and gene transcriptional effects. These new discoveries help clarify some of neural plasticity deficits seen in AS.

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