Molecular investigation of Angelman syndrome in Greece. Screening for UBE3A mutations: preliminary results

Background Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by mental retardation, absence of speech, ataxia, seizures and hyperactivity. Individuals with AS lack a normal active maternal copy of the UBE3A gene, encoding ubiquitin protein ligase (E6AP). In 80% of patients the clinical diagnosis is verified by molecular detection of one of the typical 15q11-q13 abnormalities, including chromosomal deletions (70%), paternal uniparental disomy (35%) or imprinting centre mutations (7%). Heterozygous lossoffunction mutations of E6AP have been identified in approximately 8% of cases. UBE3A gene is imprinted in human brain, with the paternal allele being normally silenced. E6AP is a member of E3 ubiquitin ligase protein family which plays a role in defining substrate specificity of the ubiquitinproteasome degradation system. The exact mechanism by which the defective E6-AP gene causes AS remains unknown. Clinical findings seem to be due to failure to degrade various proteins, accumulation of which may be harmful for an individual.