Angelman Syndrome

Pathogenic mechanisms

The Ube3a gene has been identified as the causative gene of Angelman syndrome. It is paternally imprinted (i.e. silenced) in mature neurons, therefore mutations or absence of the maternal allele result in AS. This gene can be affected in four ways: large deletions in the gene region, inheriting two copies of the gene from one parent (uniparental disomy), imprinting defects, or mutations directly within the Ube3a gene. The UBE3A protein is an E3 ubiquitin ligase, an enzyme that attaches ubiquitin moieties to its targets, labelling them for destruction, altered localization, or to impact their function. Loss of its function therefore results in accumulation of its targets that likely contribute to disease pathogenesis. Abnormalities in Ube3a expression may impact various brain regions involved in motor coordination, cognition, and behaviour. These pathogenic mechanisms underscore the intricate genetic basis of AS and its associated clinical manifestations.