UBE3A

UBE3A

Overview

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classDef protein fill:#0a1929,stroke:#2196f3
classDef disease fill:#2d0f0f,stroke:#e91e63
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UBE3A["UBE3A"] -->|"implicated_in"| neurodegeneration["neurodegeneration"]
UBE3A["UBE3A"] -->|"contributes_to"| CREB3["CREB3"]
UBE3A["UBE3A"] -->|"regulates"| ALPHA_SYNUCLEIN["ALPHA-SYNUCLEIN"]
UBE3A["UBE3A"] -->|"regulates"| PARKIN["PARKIN"]
UBE3A["UBE3A"] -->|"regulates"| UBIQUITIN["UBIQUITIN"]
UBE3A["UBE3A"] -->|"regulates"| PARK6["PARK6"]
UBE3A["UBE3A"] -->|"regulates"| MITOPHAGY["MITOPHAGY"]
UBE3A["UBE3A"] -->|"contributes_to"| MAPK8["MAPK8"]
UBE3A["UBE3A"] -->|"regulates"| ASTROCYTES["ASTROCYTES"]
UBE3A["UBE3A"] -->|"contributes_to"| NFKBIA["NFKBIA"]
UBE3A["UBE3A"] -->|"regulates"| GFAP["GFAP"]
UBE3A["UBE3A"] -->|"regulates"| NEUROINFLAMMATION["NEUROINFLAMMATION"]
UBE3A["UBE3A"] -->|"regulates"| PINK1["PINK1"]
UBE3A["UBE3A"] -->|"regulates"| Parkinson["Parkinson"]
UBE3A["UBE3A"] -->|"regulates"| Ms["Ms"]
UBE3A["UBE3A"] -->|"regulates"| Neuroinflammation["Neuroinflammation"]
UBE3A["UBE3A"] -->|"regulates"| Inflammation["Inflammation"]
UBE3A["UBE3A"] -->|"regulates"| Er_Stress["Er Stress"]
UBE3A["UBE3A"] -->|"regulates"| Innate_Immunity["Innate Immunity"]
UBE3A["UBE3A"] -->|"regulates"| Mitophagy["Mitophagy"]
UBE3A["UBE3A"] -->|"contributes_to"| Mapk["

UBE3A

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">UBE3A</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>UBE3A</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q11.2</td>
</tr>
<tr>
<td class="label">Genomic Coordinates</td>
<td>chr15:25,310,000-25,420,000 (GRCh38)</td>
</tr>
<tr>
<td class="label">Gene Length</td>
<td>~120 kb</td>
</tr>
<tr>
<td class="label">Number of Exons</td>
<td>11 coding exons</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>865 amino acids</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>E3 ubiquitin ligase (HECT family)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain (neurons), widespread peripheral tissue</td>
</tr>
<tr>
<td class="label">Imprinting</td>
<td>Maternal expression in neurons; biallelic in most peripheral tissues</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>601623</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q05086</td>
</tr>
<tr>
<td class="label">Disorder</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Angelman syndrome</td>
<td>Maternal UBE3A loss (deletion, mutation, imprinting)</td>
</tr>
<tr>
<td class="label">Angelman syndrome ( imprinting defect)</td>
<td>Paternal-only UBE3A (bipaternal inheritance)</td>
</tr>
<tr>
<td class="label">15q11.2-q13 duplication syndrome</td>
<td>Paternal UBE3A duplication</td>
</tr>
<tr>
<td class="label">Paternal UBE3A triplication</td>
<td>Extra paternal UBE3A copy</td>
</tr>
</table>

[UBE3A](/entities/ube3a) encodes UBE3A, an E3 ubiquitin-protein ligase that catalyzes the transfer of ubiquitin to substrate proteins, marking them for degradation via the proteasome or for non-degradative signaling. The gene is uniquely subject to genomic imprinting — it is expressed exclusively from the maternal allele in neurons, while the paternal allele is silenced by a long antisense transcript (UBE3A-ATS). This parent-of-origin expression pattern means that loss of the maternal UBE3A copy leads to Angelman syndrome, while duplication of the paternal copy is associated with autism spectrum disorder. PMID: 39475571

[UBE3A](/entities/ube3a) is critical for synaptic function, learning, and memory. Its key neuronal substrate is Arc (activity-regulated cytoskeleton-associated protein), which is essential for AMPA receptor trafficking and synaptic plasticity. Loss of UBE3A leads to Arc accumulation, disrupted synaptic scaling, and impairments in learning["@mabb2011"][@greer2010]. PMID: 26250687

Gene Information

Structure and Function

Protein Domains

UBE3A contains several key functional regions:

• HERC2 interaction domain — mediates binding to HERC2, which regulates UBE3A subcellular localization
• HECT domain — the catalytic domain (~350 aa) that transfers ubiquitin to substrates
• SH3 domain (variant isoforms) — protein-protein interaction motif
• Nuclear localization signals — multiple NLS sequences for nuclear/cytoplasmic shuttling PMID: 29874566

Ubiquitin Ligase Activity

UBE3A functions as a substrate-specific E3 ligase. Its canonical activity involves: PMID: 32755557

Ubiquitination can result in:

• Proteasomal degradation (K48-linked chains)
• Lysosomal degradation (K63-linked chains)
• Non-degradative signaling (monoubiquitination, other linkages)

Genomic Imprinting

The neuron-specific imprinting of [UBE3A](/entities/ube3a) is controlled by the imprinted locus on chromosome 15q11.2:

• Maternal allele: expressed in neurons — the active copy
• Paternal allele: silenced by UBE3A-ATS (antisense transcript) — the silent copy
• Non-neuronal tissues: [UBE3A](/entities/ube3a) is biallelically expressed (paternal copy is active)

Pathophysiology in Angelman Syndrome

Molecular Mechanisms

Loss of maternal [UBE3A](/entities/ube3a) leads to a cascade of downstream effects:

Critical Period for Therapeutic Intervention

Preclinical studies in Ube3a mouse models demonstrate that:

• Earlier intervention yields better outcomes
• There is a "critical period" for cerebellar plasticity (approximately weeks 3-6 in mice, corresponding to early childhood in humans)
• Direct ASIC delivery of UBE3A to young mice can rescue behavioral phenotypes; delivery to older mice shows more limited effects

Disease Associations

Genotype-Phenotype Correlations

• ~70% of Angelman cases: 5-7 Mb maternal deletion of 15q11.2-q13 — typically most severe
• ~10-15%: paternal uniparental disomy (UPD) — same phenotype but no deletion
• ~5-10%: UBE3A mutation — same phenotype
• ~5%: imprinting center defect — same phenotype
• Patients with deletions often have more severe epilepsy and motor impairment than those with mutations

Therapeutic Approaches

Genetic Therapy

GTX-102 (GeneTx/Ultragenyx) — AAV9-delivered antisense oligonucleotide targeting UBE3A-ATS to reactivate the silenced paternal allele. By suppressing the antisense transcript, GTX-102 aims to "unsilence" the paternal UBE3A, restoring functional protein levels. Currently in Phase 1/2 clinical trials. See [GTX-102 clinical trial page](/clinical-trials/gtx102-angelman-syndrome-phase-1-2).

ASO Mechanism

The paternal [UBE3A](/entities/ube3a) gene is intact but silenced by the UBE3A-ATS antisense transcript, which spans the imprinted locus and blocks paternal expression. ASOs targeting UBE3A-ATS can:

Alternative Approaches

• Gene replacement: AAV-delivered functional UBE3A — challenged by gene size (~2.6 kb coding)
• Protein replacement: Not feasible due to size and blood-brain barrier
• Small molecule activation: Topoisomerase inhibitors (doxorubicin) can unsilence paternal UBE3A in vitro but are too toxic for clinical use
• Epigenetic editing: CRISPR-based approaches to modify imprinting center methylation — preclinical

Urgent vs. Chronic Treatment

Angelman syndrome presents a unique therapeutic window challenge:

• Early intervention: Critical period for synaptic development and cerebellar plasticity suggests treatment should be initiated as early as possible
• Chronic treatment: The paternal allele silencing mechanism is persistent, so ongoing ASO therapy may be required
• ASO delivery: Intrathecal (IT) or intracerebroventricular (ICV) delivery required to achieve sufficient CNS concentrations

Research and Open Questions

References

Pathway Diagram

The following diagram shows the key molecular relationships involving UBE3A discovered through SciDEX knowledge graph analysis: