Neurodevelopmental Underpinnings of Angelman Syndrome

Abstract

This review briefly discusses key recent research literature on Angelman Syndrome (AS), a rare genetic disorder of neurodevelopmental origin. Dysfunction/inactivation of the maternal UBE3A gene and its surrounding chromosome regions has been identified as the causative factor for AS. The human UBE3A gene is located within human chromosome 15q11-13 and encodes an E3 ubiquitin-protein ligase (UBE3A, also called E6 associated protein, E6-AP). Due to genetic imprinting of the paternal copy of UBE3A gene in many brain regions, loss of function of a single maternal copy of UBE3A is highly penetrant and pathogenic. Most of the deficits seen in AS patients have been reproduced in Ube3a gene maternal deficiency mice (‘AS mice’, Ube3am−/p+), thus enabling mechanistic interrogations of AS pathogenesis and therapeutic explorations using mice models. Here we briefly discuss recent advances on AS etiology and identify some challenges in translating mechanistic insights into potential therapeutic interventions. Experimental evidence collected so far indicate impaired maternal UBE3A in neurons may contribute to AS deficiency by influencing multifaceted neural developmental processes including cell survival, synaptic transmission, signal transduction, gene expressions.