UBE3A Dosage Imbalance as a Molecular Framework Linking Angelman Syndrome and Dup15q-Associated Autism Phenotypes.

Authors

Ruslan Kurmashev

Published in

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

UBE3A is a dosage-sensitive HECT E3 ubiquitin ligase whose neuronal expression is shaped by genomic imprinting at the 15q11.2-q13 locus. Opposite directions of UBE3A dosage imbalance contribute to distinct neurodevelopmental phenotypes: loss of maternal UBE3A underlies Angelman syndrome, whereas maternally derived 15q11.2-q13 copy-number gains, including interstitial duplications and isodicentric inv. dup(15)/idic(15) rearrangements, contribute to Dup15q-associated syndromic autism phenotypes. This review synthesizes evidence across molecular architecture, isoform biology, neuronal imprinting, synaptic regulation, circuit excitability, and therapeutic development. The central argument is that UBE3A should not be interpreted as a general explanation for autism, but as a mechanistically informative model for a defined subset of neurodevelopmental disorders in which parent-of-origin effects and copy-number state are central. In Angelman syndrome, UBE3A loss disrupts proteostasis, synaptic plasticity, inhibitory circuit function, and neuronal excitability through distributed rather than single-pathway mechanisms. In the maternally derived Dup15q spectrum, increased UBE3A dosage is strongly implicated in neuronal and synaptic abnormalities, although interval-wide dosage effects also contribute. Therapeutically, the direction of dosage change creates opposite translational requirements: restoration or paternal reactivation in Angelman syndrome versus dosage normalization in Dup15q-associated overdosage states. A dosage-directionality framework may therefore clarify how UBE3A biology connects molecular mechanism, developmental timing, and precision therapeutic design.

PMID:
42464451
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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