University of Oulu

The EMBO Journal (2022) 41: e105531

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis

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Author: Medinas, Danilo Bilches1,2,3; Malik, Sajid4; Yıldız-Bölükbaşı, Esra5;
Organizations: 1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
2FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
3Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
4Human Genetics Program, Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
5Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey
6Program of Integrative Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
7Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
8Laboratory of Neuroscience, Department of Biology, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile
9Department of Chemistry, Vanderbilt University, Nashville, TN, USA
10Laboratory of Cell and Neuronal Dynamics (CENEDYN), Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile
11Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
12Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
13Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
14Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA
15Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile
16Buck Institute for Research on Aging, Novato, CA, USA
17Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
18Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.6 MB)
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Language: English
Published: EMBO Press, 2022
Publish Date: 2023-01-31


Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

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Series: EMBO journal
ISSN: 0261-4189
ISSN-E: 1460-2075
ISSN-L: 0261-4189
Volume: 41
Issue: 2
Article number: e105531
DOI: 10.15252/embj.2020105531
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was funded by FONDECYT 1191538 (DBM), FONDECYT 1200459 (UW), FONDECYT 11180825 (HU), FONDECYT 11140430 and DICYT 021843RS (CR), FONDECYT 1161524, DICYT 021843MM and 021943MM_POSTDOC (BM), FONDECYT 1180419 (CG-B), CONICYT PIA ACT 192015, FONDEQUIP EQM130051 and Nucleus Physics of Active Matter (MLC), FONDECYT 1140549 (CH), FONDAP program 15150012 (CG-B, MLC, CH), Millennium Institute P09-015-F (MLC, CH), European Commission R&D MSCA-RISE 734749 (CH), URF-QAU Pakistan (SMalik), AOF 318182 and Biocenter Oulu (LWR), and Boğaziçi University Research Fund project 7695 (AT). We also thank the support from Muscular Dystrophy Association 575897 and ALS Association 19-IIA-456 (DBM), FONDEF ID16I10223, FONDEF ID11E1007, Michael J Fox Foundation for Parkinson's Research—Target Validation grant 9277, US Office of Naval Research-Global N62909-16-1-2003, US Air Force Office of Scientific Research FA9550-16-1-0384, and Department of Defense W81XWH2110960 (CH).
Academy of Finland Grant Number: 318182
Detailed Information: 318182 (Academy of Finland Funding decision)
Copyright information: © 2021 MRC Laboratory of Molecular Biology. Published under the terms of the CC BY 4.0 license.