ArticleNature communications2021
Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.Molecular systems biology · 2026Article
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- Review
- Crossing the finish line towards a disease-modifying treatment for Angelman syndrome.Journal of neurodevelopmental disorders · 2026Review
- WWP1 gain-of-function drives developmental anoikis through TGFβ pathway during neurodevelopment.Cell death discovery · 2026Article
- Article
- Autism and intellectual disability due to a novel gain-of-function mutation in UBE3A.Journal of human genetics · 2025Article
- The gain-of-function UBE3AScientific reports · 2025Article
- Unraveling the Roles of UBE3A in Neurodevelopment and Neurodegeneration.International journal of molecular sciences · 2025Review
- Role of androgen receptors in sexually dimorphic phenotypes in UBE3A-dependent autism spectrum disorder.iScience · 2025Article
- Sex-biasing influence of autism-associatedScience advances · 2024Article
- Developmental milestones and daily living skills in individuals with Angelman syndrome.Journal of neurodevelopmental disorders · 2024Article
- Sexually dimorphic phenotypes and the role of androgen receptors in UBE3A-dependent autism spectrum disorder.bioRxiv : the preprint server for biology · 2024Article
- Structural insights into the functional mechanism of the ubiquitin ligase E6AP.Nature communications · 2024Article
- mRNA nuclear retention reduces AMPAR expression and promotes autistic behavior in UBE3A-overexpressing mice.EMBO reports · 2024Article
- An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.American journal of human genetics · 2023Article
- Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice.Cell reports · 2023Article
- Structural and Pathogenic Impacts ofInternational journal of molecular sciences · 2023Article
- Stem cell models of Angelman syndrome.Frontiers in cell and developmental biology · 2023Review
- A Scalable, Cell-based Method for the Functional Assessment of Ube3a Variants.Journal of visualized experiments : JoVE · 2022Article
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13 authors.
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Abstract
The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders.
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