ArticleHuman molecular genetics2021
Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations.
Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 33 citations in OpenAlex.
- Cell-type-specific dysregulated gene expression in the frontal cortex of an Angelman syndrome pig model.Human molecular genetics · 2026Article
- UBE3A isoform-selective and non-selective contributions to Angelman syndrome phenotypes.Molecular psychiatry · 2026Article
- Crossing the finish line towards a disease-modifying treatment for Angelman syndrome.Journal of neurodevelopmental disorders · 2026Review
- From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.Frontiers in epigenetics and epigenomics · 2026Review
- E3 ubiquitin ligases: structural diversity, dysregulation in disease, and their emerging role in targeted therapeutic strategies.Frontiers in molecular biosciences · 2026Review
- Article
- UBE3A promotes foam cell formation and counters remyelination by targeting ABCA1 for proteasomal degradation.Nature communications · 2025Article
- Article
- Identification of E3 Ubiquitin Ligase Substrates Using Biotin Ligase-Based Proximity Labeling Approaches.Biomedicines · 2025Review
- The gain-of-function UBE3AScientific reports · 2025Article
- Neuronal UBE3A substrates hold therapeutic potential for Angelman syndrome.Current opinion in neurobiology · 2024Review
- Sex-biasing influence of autism-associatedScience advances · 2024Article
- The role of glia in the dysregulation of neuronal spinogenesis in Ube3a-dependent ASD.Experimental neurology · 2024Article
- A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Novel epigenetic molecular therapies for imprinting disorders.Molecular psychiatry · 2023Review
- Stem cell models of Angelman syndrome.Frontiers in cell and developmental biology · 2023Review
- The Hippocampal Response to Acute Corticosterone Elevation Is Altered in a Mouse Model for Angelman Syndrome.International journal of molecular sciences · 2022Article
- Promising therapeutic aspects in human genetic imprinting disorders.Clinical epigenetics · 2022Review
- A Scalable, Cell-based Method for the Functional Assessment of Ube3a Variants.Journal of visualized experiments : JoVE · 2022Article
- Molecular and behavioral consequences of Ube3a gene overdosage in mice.JCI insight · 2022Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.
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