From Genomic Imprinting to Developmental Physiology: Identifying Stepping Stones

Genomic imprinting is a process that determines differential expression of genes according to their parental origin. Most imprinted genes play roles in growth, development and tumour suppression. Angelman syndrome is one of the most studied human diseases related to a gene that is expressed on the maternal chromosome only (at least in certain brain cells). It is caused by inactivation of the UBE3A gene in the brain due to various abnormalities of chromosome 15q11-q13 inherited from the mother. Its phenotype includes developmental delay, absent speech, motor impairment, a typical electroencephalogram, seizures and a peculiar behaviour. Lack of UBE3A expression may result from deletion of the 15q11-q13 region where this gene and GABRB3 are located, paternal uniparental disomy, imprinting defect or UBE3A mutation. Animal models corresponding to the different molecular classes have been generated. An integrative hypothesis for the molecular pathophysiology of the syndrome suggests dysregulation of synaptic neurotransmission through UBE3A-related modulation of functional GABAA receptors and GABRB3-related amount of β3 sub-unit in these receptors. This would account for developmental changes as well as for the differences in severity between deletion and nondeletion cases. In addition to rehabilitation programmes adapted to the patients' individual needs, promising management approaches may include pharmacological agents interfering with GABAA receptors, increasing GABRB3 expression or altering DNA methylation.