PXD026507

PXD026507 is an original dataset announced via ProteomeXchange.

Title	Mutant PDIA3 causes neurodevelopmental impairment by disturbing endoplasmic reticulum proteostasis
Description	Identification of a disease gene enables the elucidation of the gene function in biological networks. Here we report homozygous c.170G>A (p.Cys57Tyr or C57Y) in protein disulfide isomerase A3 (PDIA3) causing syndromic intellectual disability. PDIA3 catalyzes the formation of disulfide bonds in the endoplasmic reticulum. Experiments in zebrafish embryos showed that PDIA3C57Y is pathogenic, causing developmental problems such as axonal disorganization and skeleton abnormalities. In mammalian models, expression of PDIA3C57Y inhibited axonal growth and impaired synaptic plasticity and memory consolidation. Proteomic and functional analysis revealed that PDIA3C57Y leads to dysregulation of cell adhesion and actin cytoskeleton dynamics associated with altered integrin biogenesis. These alterations were correlated with low catalytic activity of PDIA3C57Y, which also forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. This study shows that the disturbance of the proteostasis network in intellectual disability cases adversely impacts cellular connectivity and neuronal function, constituting a pathogenic pathway to neurodevelopmental impairment.
HostingRepository	PRIDE
AnnounceDate	2021-11-25
AnnouncementXML	Submission_2021-11-25_08:15:14.476.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Madison Wright
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-06 22:04:09	ID requested
⏵ 1	2021-11-25 08:15:14	announced

Dataset with its publication pending

submitter keyword: intellectual disability / cell adhesion / actin cytoskeleton / integrins / protein disulfide isomerase

Danilo B. Medinas
contact affiliation	Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
contact email	danilo.medinas@gmail.com
lab head
Madison Wright
contact affiliation	Vanderbilt University Department of Chemistry
contact email	madison.t.wright@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026507
     1. Label: PRIDE project
     2. Name: Mutant PDIA3 causes neurodevelopmental impairment by disturbing endoplasmic reticulum proteostasis