Hyperactive UBE3A Variants Cause Neomorphic Neurodevelopmental Phenotypes

ABSTRACT: Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in heterogeneous disease phenotypes in humans which differ from classic Angelman syndrome. We describe two affected siblings who possess an inherited UBE3AL734S variant that causes a strong gain in UBE3A activity. Unlike previously described cases, these individuals exhibited borderline microcephaly, suggesting the extent of UBE3A gain-of-function can produce neomorphic phenotypes. Here, we characterize a mouse model harboring a strong gain of function variant (Ube3aQ606E) which elevates UBE3A activity 388% above wild type (WT) enzyme levels. We conduct extensive behavioral phenotyping to show that Ube3amQ606E mutants show motor deficits, hypoactivity, and reduced stereotypic behaviors. Brain weights and MRI analysis revealed global microcephaly with a postnatal onset. Proteomic analysis performed on neonatal cortex revealed perturbations in several key proteins and pathways linked to neurodevelopmental disease. Finally, we show that microcephaly is not caused by increased apoptotic cell death. Together, our results provide strong evidence that the type and severity of disease phenotypes depend on the causative UBE3A gain of function mutation and provide new insights into the phenotypic heterogeneity observed in individuals with UBE3A gain of function variants.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Tissue, Brain

SUBMITTER: Dennis Goldfarb  

LAB HEAD: Jason Yi

PROVIDER: PXD055901 | Pride | 2025-05-07

REPOSITORIES: Pride