Angelman syndrome: Drugs to awaken a paternal gene

Abstract

Mutations in the maternal copy of the UBE3A gene cause a neurodevelopmental disorder known as Angelman syndrome. Drugs that activate the normally silenced paternal copy of this gene may be of therapeutic value.

Figure 1. Differential regulation of maternal and paternal UBE3A

Of the two copies of the UBE3A gene, only the maternal copy is expressed in neurons, with the paternal copy being silenced by genomic imprinting. Specifically, expression of paternal UBE3A is inhibited by transcription in the antisense direction of a long sequence that includes not only this gene but also the control centre that regulates its expression. In the equivalent maternal chromosome, the sequence encoding the control centre is methylated (Me) and so is not expressed. This inhibits transcription in the antisense direction and allows expression of UBE3A. Huang et al. identify drugs that can activate expression of paternal UBE3A. Such drugs could be useful for treating Angelman syndrome, a disorder in which maternal UBE3A expression is absent or very low.