Journal
HUMAN MOLECULAR GENETICS
Volume 26, Issue 20, Pages 3995-4010Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx289
Keywords
-
Funding
- Dup15q Alliance
- Simon's Foundation for Autism Research Initiative
- Autism Science Foundation
- Texas A&M AgriLife Research
- Foundation for Angelman Syndrome Therapeutics (SBC)
- MIND Institute
- NIH [R01NS097808, R01ES021707]
- Canadian Institute for Health Research
- Ontario Brain Institute
- MIND Institute's Intellectual and Developmental Disabilities Research Center (IDDRC) [HD079125]
Ask authors/readers for more resources
Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. Dup15q syndrome is one of the most common and penetrant chromosomal abnormalities observed in individuals with autism spectrum disorder (ASD). Although similar to 40 genes are located in the 15q11.2-q13.3 region, overexpression of the ubiquitin-protein E3A ligase (UBE3A) gene is thought to be the predominant molecular cause of the phenotypes observed in Dup15q syndrome. The UBE3A gene demonstrates maternal-specific expression in neurons and loss of maternal UBE3A causes Angelman syndrome, a neurodevelopmental disorder with some overlapping neurological features to Dup15q. To directly test the hypothesis that overexpression of UBE3A is an important underlying molecular cause of neurodevelopmental dysfunction, we developed and characterized a mouse overexpressing Ube3a isoform 2 in excitatory neurons. Ube3a isoform 2 is conserved between mouse and human and known to play key roles in neuronal function. Transgenic mice overexpressing Ube3a isoform 2 in excitatory forebrain neurons exhibited increased anxiety-like behaviors, learning impairments, and reduced seizure thresholds. However, these transgenic mice displayed normal social approach, social interactions, and repetitive motor stereotypies that are relevant to ASD. Reduced forebrain, hippocampus, striatum, amygdala, and cortical volume were also observed. Altogether, these findings show neuronal overexpression of Ube3a isoform 2 causes phenotypes translatable to neurodevelopmental disorders.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available