# Investigating UBE3A as a driver gene in Duplication 15q syndrome

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $392,239

## Abstract

PROJECT SUMMARY
Maternal duplication of the chromosome 15q11-q13 locus (Dup15q syndrome) is a major genetic cause of
autism spectrum disorder. UBE3A is contained within this genetic locus; compelling evidence suggests it is the
main driver of Dup15q syndrome pathophysiology. Accordingly, the normalization of UBE3A levels might
effectively treat the syndrome, but this has been difficult to test. To allow us to test this idea, we have
generated conditional Ube3a-overexpression mice that have construct validity for the principal cytogenetic
abnormalities underlying Dup15q syndrome: interstitial chromosome 15 duplication (1 extra copy of Ube3a)
and isodicentric chromosome 15 (2 extra copies of Ube3a). Thus, our models will be valuable for determining
the extent to which increases in UBE3A protein levels are necessary and sufficient to drive Dup15q-relevant
pathophysiology. With these mice, we are also able to genetically normalize Ube3a expression at different
ages, allowing us to identify the window during which normalization provides substantial therapeutic benefit. To
advance an informed intervention strategy for Dup15q syndrome, we will use our new mouse models to (1)
establish the behavioral and physiological consequences of UBE3A overexpression, (2) determine when
normalization of UBE3A rescues pathophysiology, and (3) optimize an approach to appropriately knock down
UBE3A and correct pathophysiology in Ube3a-overexpression mice.

## Key facts

- **NIH application ID:** 10791919
- **Project number:** 5R01NS129914-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** BENJAMIN D PHILPOT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $392,239
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791919

## Citation

> US National Institutes of Health, RePORTER application 10791919, Investigating UBE3A as a driver gene in Duplication 15q syndrome (5R01NS129914-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10791919. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*