# Phenotypic Characterization of Novel Models of Dup15q Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $343,438

## Abstract

Project Summary
Maternally derived duplications or triplications of 15q11.2-q13 (Dup15q) are one of the most
common genetic variations associated with autism spectrum disorder (ASD), detected in 1-3%
of cases. Prominent features commonly found in Dup15q include intellectual disability (ID),
epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features.
The ubiquitin E3A ligase gene (UBE3A), which maps to the 15q11.2-q13 region, has been
implicated in multiple neurodevelopmental disorders, including ASD, Angelman Syndrome (AS),
Prader-Willi Syndrome (PWS) and ID. Based on this information, we postulate that dysregulated
UBE3A has deleterious outcomes. Because UBE3A is imprinted specifically in neurons, we will
use novel mouse models to test the hypothesis that elevated UBE3A in neurons is the major
contributor to phenotypes. It is well known that three differentially spliced isoforms of UBE3A
exist, propelling us to pursue the secondary scientific question of which isoform plays the most
critical role in Dup15q. No in vivo studies, to date, have evaluated the phenotypic contributions
associated with each of the three Ube3a isoforms. Preliminary data illustrate our discovery that
forebrain, neuronal selective overexpression of Ube3a isoform 2 is sufficient to cause behavioral
and anatomical phenotypes. Here, we propose a multifaceted, collaborative project to identify
behavior, neuroanatomical and epigenetic mechanisms of isoform-specific Ube3a
overexpression. This proposal will directly address the most important questions regarding our
main scientific premise that overexpression of UBE3A is the principal pathogenic mechanism
causing Dup15q impairments. We will also address our secondary premise, that different
Ube3a isoforms in neurons cause differential behavioral, pathological and epigenetic anomalies.
We will delineate phenotypes and identify pathologies in each line of isoform-specific Ube3a-
overexpressing mice. Significant correlations and corroborations between molecular, cellular,
histopathological and behavioral phenotypes will reveal key information on neural substrates of
Dup15q phenotypes. These studies will answer the most important questions regarding the
pathogenic nature of mechanisms underlying UBE3A overexpression.

## Key facts

- **NIH application ID:** 10085262
- **Project number:** 5R01NS097808-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Jill Lynn Silverman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,438
- **Award type:** 5
- **Project period:** 2017-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085262

## Citation

> US National Institutes of Health, RePORTER application 10085262, Phenotypic Characterization of Novel Models of Dup15q Syndrome (5R01NS097808-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10085262. Licensed CC0.

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