Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the UBE3A gene is presumed to be the primary driver of Dup15q pathophysiology, given that UBE3A exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. In contrast to previously published Ube3a overexpression models, Ube3aOE mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between UBE3A and other overexpressed 15q11.2-q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes.
This work was supported by NWO-ZonMw TOP grant 91216045 to YE, NIH K99EY028964 to MSS,
and NIH R01MH120229, NIH R01NS114086, NIH R01NS129914, Simons Foundation Autism Research
Initiative award 702556, and an award from the Dup15Q Alliance to BDP. BNW was funded by a postdoctoral training grant (NIH T32HD040127) and holds a Postdoctoral Enrichment Program Award from the
Burroughs Wellcome Fund. Microscopy was performed at the University of North Carolina (UNC) Neuroscience Microscopy Core Facility, supported, in part, by funding from NIH/National Institute of Neurological Disorders and Stroke Neuroscience Center Support Grant P30NS045892 and the UNC Intellectual
and Developmental Disabilities Research Center (NIH/National Institute of Child Health and Human