Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uni-parental disomy, translocation, or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from mother, the other from father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sex-related epigenetic imprinting; the biochemical mechanism is DNA methylation. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.)
Angelman syndrome can also be the result of mutation of a single gene. This gene (Ube3a, part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (Imprinting). The paternal silencing of the Ube3a gene occurs in a brain region-specific manner; the maternal allele is active almost exclusively in the hippocampus and cerebellum. The most common genetic defect leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing an absence of Ube3a expression in the maternally imprinted brain regions. Ube3a codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying the human Angelman syndrome mental retardation state.
Initial studies of mice that do not express maternal Ube3a show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a -/- mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vitro, and the molecular pathology of Angelman syndrome.