Kathryn Kuczkowski

Background: Autism Spectrum Disorders (ASD) are developmental disorders characterized by variable levels of social skills, impaired communication, and repetitive behaviors. It’s estimated that epilepsy co-occurs in 15% of individuals diagnosed with ASD.¹ One genetic mechanism being evaluated in linking ASD and epilepsy is maternal overexpression of chromosome 15q11-q13 known as Dup15q syndrome.² Of individuals diagnosed with Dup15q syndrome, 77-100% were diagnosed with ASD and approximately 63% also had epilepsy.³ UBE3A is the only gene in the 15q11-q13 region where the paternal copy is imprinted and the maternal copy is exclusively expressed, therefore it is overexpressed only in maternal Dup15q syndrome.⁴ UBE3A encodes a ubiquitin E3 ligase enzyme (E6AP) that functions in targeting proteins for degradation by proteasomes, regulating synaptic function, and forming memories²

Objective: In this narrative review, we explored the mechanisms by which UBE3A may contribute to Dup15q and epileptic phenotypes.

Search Methods: A search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “Autism”, ” Epilepsy”, “UBE3A”, “Dup15q”.

Results: In a comparative patient study between Dup15q syndrome subtypes, symptom severity and epilepsy prevalence directly correlated with UBE3A gene dosage. These results created a range of phenotypes where individuals with an interstitial duplication without epilepsy had the fewest impairments, and those with an isodicentric triplication with epilepsy had the most severe impairments.³ Overexpression of the UBE3A gene and subsequent E6AP product were linked to aberrant remodeling during neuronal dendrite development. Specifically, UBE3A+ neuron dendrites were fewer in total number, length, and non-primary branches due to excessive remodeling by UBE3A/E6AP in the ubiquitination/proteasome degradation pathway.⁴ Experiments using whole-cell patch-clamp testing concluded that UBE3A+ neurons transported significantly more sodium and potassium ions across the cell membrane. Unsurprisingly, these increased ion currents correlated with an increase in action potential (AP) firing and a significantly lowered AP threshold.⁵ In a similar experiment, the rate of spontaneous AP firing was compared between Dup15q+ and control neurons using whole-cell patch-clamp testing. This study concluded that Dup15q+ neurons fired significantly more spontaneous AP at nearly three times the rate of the control neurons.² In contrast to these findings, an experiment using a bacterial transgenic mouse model to over express UBE3A failed to detect significant cellular or behavioral phenotypic differences between wild type and UBE3A+ mice. Additionally, when seizures were induced in the mice, it was determined that UBE3A+ mice did not exhibit a significantly lowered seizure threshold compared to wild type mice.⁶ While several experiments had statistically significant differences between UBE3A+ and control groups, the cellular and behavioral phenotypes were only similar, not identical to Dup15q phenotypes in each of the studies.

Conclusion: The hyperexcitability, aberrant connectivity, and increased frequency of spontaneous AP in Dup15q/UBE3A+ neurons support that overexpression of UBE3A contributes to increased seizure activity. However, UBE3A does not seem to be solely responsible for cellular, electrophysiological, and behavioral phenotypes of ASD, Dup15q syndrome, and epilepsy. Further research remains on UBE3A overexpression, Dup15q subtypes, and the genetic link between seizures and ASDs.

Works Cited:

1. Brondino N, Fusar-Poli L, Miceli E, et al. Prevalence of Medical Comorbidities in Adults with Autism Spectrum Disorder. J Gen Intern Med. 2019;34(10):1992-1994. doi:10.1007/s11606-019-05071-x
2. Fink JJ, Schreiner JD, Bloom JE, et al. Hyperexcitable Phenotypes in Induced Pluripotent Stem Cell-Derived Neurons From Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism. Biol Psychiatry. 2021;90(11):756-765. doi:10.1016/j.biopsych.2021.07.018
3. DiStefano C, Wilson RB, Hyde C, et al. Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials. Am J Med Genet A. 2020;182(1):71-84. doi:10.1002/ajmg.a.61385
4. Khatri N, Gilbert JP, Huo Y, et al. The Autism Protein Ube3A/E6AP Remodels Neuronal Dendritic Arborization via Caspase-Dependent Microtubule Destabilization. J Neurosci. 2018;38(2):363-378. doi:10.1523/JNEUROSCI.1511-17.2017
5. Elamin M, Dumarchey A, Stoddard C, et al. The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons. Stem Cell Reports. 2023;18(4):884-898. doi:10.1016/j.stemcr.2023.02.002
6. Punt AM, Judson MC, Sidorov MS, et al. Molecular and behavioral consequences of Ube3a gene overdosage in mice. JCI Insight. 2022;7(18):e158953. Published 2022 Sep 22. doi:10.1172/jci.insight.158953