# Understanding the mechanisms of UBE3A regulation in neuronal development

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $393,750

## Abstract

Abstract. UBE3A is a gene that encodes a HECT (Homologous to E6AP C-terminus) domain E3 ubiquitin ligase
linked to numerous developmental and psychiatric disorders. Loss of function of the maternally derived UBE3A
enzyme causes Angelman syndrome whereas gain of function, due to duplication or triplication of UBE3A, is
linked to a broad range of disorders including Dup15q syndrome, schizophrenia, and mood disorders. These
observations strongly suggest that bi-directional changes in UBE3A activity contribute to neuropsychiatric
pathology. However, the mechanisms that regulate UBE3A activity remain poorly understood. The primary goal
of our proposed research is to uncover mechanisms of UBE3A regulation, that when faulty, can lead to aberrant
gain or loss of UBE3A function. In preliminary work, we developed a high-throughput assay to assess the
functional consequence of non-truncating UBE3A missense variants. This screen identified numerous novel
loss of function mutations, as well as gain of function mutations that hyperactivate UBE3A activity well above
wild type (WT) enzyme levels. These results provide deep structure-function information that we can now
leverage to uncover mechanisms of UBE3A regulation. This proposal aims to, 1) create a complete functional
catalogue of known missense variants identified in individuals, 2) utilize structure-function analyses to identify
mechanisms that can lead to both aberrant gain and loss of enzyme function, and 3) leverage biochemical
insights to engineer proteins that can target UBE3A activity. The molecules generated from our work will be
applied to examine whether alteration of UBE3A activity can rescue synaptic phenotypes observed in mice
harboring hyperactivating mutations in UBE3A. If successful, our work will provide new biochemical insights and
tools that will make it possible to target UBE3A for therapeutic intervention in various neuropsychiatric disorders.

## Key facts

- **NIH application ID:** 10305686
- **Project number:** 5R01MH122786-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jason J Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305686

## Citation

> US National Institutes of Health, RePORTER application 10305686, Understanding the mechanisms of UBE3A regulation in neuronal development (5R01MH122786-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10305686. Licensed CC0.

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