PXD055901

PXD055901 is an original dataset announced via ProteomeXchange.

Title	Hyperactive UBE3A Variants Cause Neomorphic Neurodevelopmental Phenotypes
Description	Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in heterogeneous disease phenotypes in humans which differ from classic Angelman syndrome. We describe two affected siblings who possess an inherited UBE3AL734S variant that causes a strong gain in UBE3A activity. Unlike previously described cases, these individuals exhibited borderline microcephaly, suggesting the extent of UBE3A gain-of-function can produce neomorphic phenotypes. Here, we characterize a mouse model harboring a strong gain of function variant (Ube3aQ606E) which elevates UBE3A activity 388% above wild type (WT) enzyme levels. We conduct extensive behavioral phenotyping to show that Ube3amQ606E mutants show motor deficits, hypoactivity, and reduced stereotypic behaviors. Brain weights and MRI analysis revealed global microcephaly with a postnatal onset. Proteomic analysis performed on neonatal cortex revealed perturbations in several key proteins and pathways linked to neurodevelopmental disease. Finally, we show that microcephaly is not caused by increased apoptotic cell death. Together, our results provide strong evidence that the type and severity of disease phenotypes depend on the causative UBE3A gain of function mutation and provide new insights into the phenotypic heterogeneity observed in individuals with UBE3A gain of function variants.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_02:56:26.851.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Goldfarb
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-16 07:37:24	ID requested
⏵ 1	2025-05-07 02:56:27	announced

10.1038/s41598-025-92511-w;

Weston KP, Gunelson AM, Maloney SE, Ge X, Stelzer JA, Kim KS, Collier S, Mindt MM, Agajanian MJ, Major MB, Goldfarb D, Noguchi KK, Yi JJ, variant causes Angelman-like neurodevelopmental phenotypes in mice. Sci Rep, 15(1):9152(2025) [pubmed]

submitter keyword: UBE3A, Autism

Jason Yi
contact affiliation	Department of Neuroscience, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA
contact email	jasonyi@wustl.edu
lab head
Dennis Goldfarb
contact affiliation	Cell Biology and Physiology Institute for Informatics
contact email	d.goldfarb@wustl.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD055901

PRIDE project URI

• PRIDE
  1. PXD055901
     1. Label: PRIDE project
     2. Name: Hyperactive UBE3A Variants Cause Neomorphic Neurodevelopmental Phenotypes