An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A
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Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis.
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Expression of the UBE3A T485A variant, identified in a patient with ASD, abolishes phosphorylation at the mutated site, increases protein activity, and causes increased spine density on basal dendrites in the somatosensory cortex.
“Expression of the UBE3A T485A variant, identified in a patient with ASD abolishes phosphorylation of UBE3A at the mutated site, results in increased activity of the protein and causes increased spine density on basal dendrites in the somatosensory cortex [396].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [396]
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- Authors
- Yi, J. J., Berrios, J., Newbern, J. M., Snider, W. D., Philpot, B. D., Hahn, K. M., & Zylka, M. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Arizona State University (US)
- Corresponding author
- Zylka, Mark J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 4
- Pages
- 795-807
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4537845
- OpenAlex
- W2106667875
- Cited by
- 177
- References
- 46
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 16 · 2023: 7 · 2022: 10 · 2021: 13 · 2020: 39 · 2019: 15 · 2018: 13 · 2017: 23 · 2016: 14 · 2015: 4
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Autism Speaks
- Angelman Syndrome Foundation
- University of Utah
- Foundation for Angelman Syndrome Therapeutics
- Simons Foundation Autism Research Initiative
- ARUP Laboratories
- National Institutes of Health (GM103723)
- National Institute of Mental Health (R01MH093372)
- National Institute of General Medical Sciences (P01GM103723, GM103723)
- National Institute of Neurological Disorders and Stroke (K99NS076661, R01NS031768, R00NS076661, R01NS085093, P30NS045892)
- National Institute of Environmental Health Sciences (DP1ES024088)
- National Institute of Biomedical Imaging and Bioengineering (P41EB002025)
- National Center for Chronic Disease Prevention and Health Promotion (DP1ES024088)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124, P30HD003110, T32HD040127)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- UBE3A, autism spectrum disorder, Angelman syndrome, protein kinase A, phosphorylation, missense mutations, ubiquitin ligase activity, dendritic spine development, synaptic dysfunction, neurodevelopmental disorders
- MeSH terms
- Animals, Autistic Disorder, Brain, Embryo, Mammalian, Enzyme Stability, Female, Humans, Mice, Inbred C57BL, Phosphorylation, Mutagenesis, Angelman Syndrome, Cyclic AMP-Dependent Protein Kinases, Mutation, Missense, Ubiquitin-Protein Ligases, Dendritic Spines
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