# Contribution of GABA-A receptor subunit deletions to Angelman syndrome pathophysiology

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2021 · $451,000

## Abstract

PROJECT SUMMARY
Individuals with a deletion of chromosome 15q11-q13 suffer from Angelman syndrome (AS), a neurogenetic
developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The
specific gene that is responsible for AS encodes the ubiquitin protein ligase UBE3A, although other genes in the
region are also deleted. AS can also result from loss of function mutations of UBE3A, which spares the other
genes located in the region. UBE3A mutation AS patients typically have a milder phenotype, especially with
regard to epilepsy and seizures. This suggests that the loss of other genes in the region, in addition to UBE3A,
likely contribute to the severe epilepsy phenotype in deletion AS patients. In particular, a cluster of genes
encoding three GABAA receptor subunits is located within the region typically deleted in AS. Reduced expression
of these subunits has been implicated in several human neurodevelopmental disorders such as Angelman
syndrome, certain syndromic forms of epilepsy, and autism. We hypothesize that hemizygous loss of GABRB3,
GABRA5, and/or GABRG3, in conjunction with loss of UBE3A expression, causes neuronal hyperexcitability and
enhanced seizure susceptibility in human AS individuals. We will test this hypothesis by comparing the
physiological phenotype of AS neurons derived from mutation and deletion AS patients. We will use antisense
oligonucleotide approaches to determine if knocking down expression of these GABA receptor subunits in a
UBE3A deficient line will confer the increased excitability seen in neurons derived from AS deletion patients.
These studies will shed light on the cellular mechanisms responsible for seizures in AS and identify targets for
development of novel therapeutics.

## Key facts

- **NIH application ID:** 10391880
- **Project number:** 1R21NS125850-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Eric S Levine
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,000
- **Award type:** 1
- **Project period:** 2021-09-20 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10391880

## Citation

> US National Institutes of Health, RePORTER application 10391880, Contribution of GABA-A receptor subunit deletions to Angelman syndrome pathophysiology (1R21NS125850-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10391880. Licensed CC0.

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