The contents of this thesis focus on Angelman Syndrome (AS), a rare neurodevelopmental disorder. More specifically, it focuses on the protein central to the disorder and its function. highlights a key difference between the different isoforms of UBE3A. This chapter exposes the difference in subcellular localization between UBE3A isoforms, and shows that mice lacking the dominant nuclear form most faithfully recapitulate the phenotypes associated with AS. Through creative use of molecular biology techniques these experiments demonstrate not only the precise mechanism through which the dominant isoform localizes to the nucleus of the cell, but also how AS-linked missense mutations abrogate this nuclear targeting. The structural requirements of the UBE3A AZUL interaction with its transport are further elucidated by highlighting the specific contributions of both UBE3A and PSMD4. Mutations causing AS are further analyzed and, showing almost half of AS-linked missense variants lead to mislocalization of UBE3A. Furthermore, by subjecting over 25 variants to a three-step functional analysis, this chapter has proposed a mutation classification system which clearly indicates that the main causes of aberrant function by UBE3A are caused either by mislocalization to the cytosol, or loss of catalytic activity in the nucleus. Concludingly, the results propose a framework where through experimental analysis, patient mutations can be grouped into specific categories.