Investigating UBE3A as a driver gene in Duplication 15q syndrome

PROJECT SUMMARY Maternal duplication of the chromosome 15q11-q13 locus (Dup15q syndrome) is a major genetic cause of autism spectrum disorder. UBE3A is contained within this genetic locus; compelling evidence suggests it is the main driver of Dup15q syndrome pathophysiology. Accordingly, the normalization of UBE3A levels might effectively treat the syndrome, but this has been difficult to test. To allow us to test this idea, we have generated conditional Ube3a-overexpression mice that have construct validity for the principal cytogenetic abnormalities underlying Dup15q syndrome: interstitial chromosome 15 duplication (1 extra copy of Ube3a) and isodicentric chromosome 15 (2 extra copies of Ube3a). Thus, our models will be valuable for determining the extent to which increases in UBE3A protein levels are necessary and sufficient to drive Dup15q-relevant pathophysiology. With these mice, we are also able to genetically normalize Ube3a expression at different ages, allowing us to identify the window during which normalization provides substantial therapeutic benefit. To advance an informed intervention strategy for Dup15q syndrome, we will use our new mouse models to (1) establish the behavioral and physiological consequences of UBE3A overexpression, (2) determine when normalization of UBE3A rescues pathophysiology, and (3) optimize an approach to appropriately knock down UBE3A and correct pathophysiology in Ube3a-overexpression mice.