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Angelman syndrome
MIM.105830 15q11-q13 and Xq28
Thursday 2 October 2003
Definition: Angelman syndrome (AS) is a neuro-genetic disorder characterized by intellectual and developmental delay, sleep disturbance, seizures, jerky movements especially hand-flapping, frequent laughter or smiling, and usually a happy demeanour.
Angelman syndrome is a classic example of genetic imprinting in that it is usually caused by deletion or inactivation of genes on the maternally inherited chromosome 15. The sister syndrome, Prader-Willi syndrome, is caused by a similar loss of paternally-inherited genes.
Physiopathology
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 uniparental disomy, translocation, or single gene mutation in that region.
A healthy person receives two copies of chromosome 15, one from the mother, the other from the 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. In a normal individual, the maternal allele is expressed and the paternal allele is silenced.
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.)
Cytogenetics
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
Angelman syndrome can also be the result of mutation of a single gene, UBE3A, coding for a protein of the ubiquitin pathway.
UBEA3 is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (parental mprinting). 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.
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.
Animal model
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.
15q11-q13 anomalies
Prader-Willi syndrome and Angelman syndrome are neurogenetic disorders that are caused by the loss of function of imprinted genes in 15q11-q13.
Prader-Willi and Angelman syndromes (PWS and AS) typically result from an approximately 4-Mb deletion of human chromosome 15q11-q13, with clustered breakpoints (BP) at either of two proximal sites (BP1 and BP2) and one distal site (BP3).
References
Mann MR, Bartolomei MS. Towards a molecular understanding of Prader-Willi and Angelman syndromes. Hum Mol Genet. 1999;8(10):1867-73. PMID: 10469839