[From pathogenesis to treatment of genetic intellectual disabilities: a lesson from Angelman syndrome research].

Abstract

Angelman syndrome (AS) is characterized by severe intellectual disability, epilepsy and ataxic motor dysfunction. Paternally imprinted UBE3A, which is located in the imprinted domain of 15q11-q13, is the causative gene of AS. UBE3A is exclusively expressed from the maternally inherited allele only in neurons (neuron-specific imprinting), and is regulated by antisense RNA. UBE3A is an E3 ubiquitin protein ligase and Arc is one of its targets in the brain. Arc is known to regulate AMPA-type glutamate receptor at the post-synaptic membrane. Loss-of-function of UBE3A results in upregulation of Arc and downregulation of AMPA receptors, giving rise to disturbance in experience-dependent synaptic plasticity. Unraveling the pathophysiology of AS will shed light on the development of pharmaceutical agents for genetic intellectual disabilities. Recently, topoisomerase inhibitors were shown to unsilence imprinted Ube3a in a mouse model of AS. This success indicated the possibility of an epigenetic therapy for AS. Therefore, AS is also a good model for the development of epigenetic therapy for genetic intellectual disorders caused by epigenetic dysfunction.