The gain-of-function UBE3A^Q588E variant causes Angelman-like neurodevelopmental phenotypes in mice.

ABSTRACT: Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in disease phenotypes which differ from classic Angelman syndrome. However, these phenotypes are highly heterogeneous raising questions about the mechanistic basis of such phenotypic diversity. Here, we characterize a mouse model harboring a Ube3a^Q606E gain of function variant (UBE3A^Q588E in humans). Extensive behavioral phenotyping showed that animals possessing a maternally inherited mutation (Ube3a^mQ606E) paradoxically show many behavioral deficits indicative of overall UBE3A loss-of-function. These included pronounced motor deficits, hypoactivity, and reduced stereotypic behaviors. Moreover, brain weights and MRI analysis revealed global microcephaly with a postnatal

SUBMITTER: Weston KP 

PROVIDER: S-EPMC11914044 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature