Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome

Nycole A. Copping, Sarah G.B. Christian, Dylan J. Ritter, M. Saharul Islam, Nathalie Buscher, Dorota Zolkowska, Michael C. Pride, Elizabeth L. Berg, Janine M. LaSalle, Jacob Ellegood, Jason P. Lerch, Lawrence T. Reiter, Jill L. Silverman, Scott V. Dindot

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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, andminor dysmorphic features. Dup15q syndrome is one of themost common and penetrant chromosomal abnormalities observed in individuals with autismspectrumdisorder (ASD). Although ~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 predominantmolecular cause of the phenotypes observed in Dup15q syndrome. The UBE3A gene demonstratesmaternal- specific expression in neurons and loss ofmaternal 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 underlyingmolecular cause of neurodevelopmental dysfunction, we developed and characterized a mouse overexpressing Ube3a isoform2 in excitatory neurons. Ube3a isoform2 is conserved betweenmouse and human and known to play key roles in neuronal function. Transgenicmice overexpressing Ube3a isoform2 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 repetitivemotor 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 isoform2 causes phenotypes translatable to neurodevelopmental disorders.

Original languageEnglish (US)
Pages (from-to)3995-4010
Number of pages16
JournalHuman Molecular Genetics
Volume26
Issue number20
DOIs
StatePublished - Oct 15 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Copping, N. A., Christian, S. G. B., Ritter, D. J., Saharul Islam, M., Buscher, N., Zolkowska, D., Pride, M. C., Berg, E. L., LaSalle, J. M., Ellegood, J., Lerch, J. P., Reiter, L. T., Silverman, J. L., & Dindot, S. V. (2017). Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome. Human Molecular Genetics, 26(20), 3995-4010. https://doi.org/10.1093/hmg/ddx289