Department
Mechanical Engineering
Document Type
Article
Publication Title
Nature communications
ISSN
2041-1723
Volume
12
Issue
1
DOI
10.1038/s41467-021-27156-0.
First Page
6809
Publication Date
Fall 1-1-2021
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Steimel, J. P.,
Weston, K.,
Gao, X.,
Zhao, J.,
Maloney, S.,
Gotoff, J.,
Parikh, S.,
Shinawi, M.,
&
Harrison, J.
(2021).
Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis.
Nature communications, 12(1), 6809.
DOI: 10.1038/s41467-021-27156-0.
https://scholarlycommons.pacific.edu/soecs-facarticles/220
