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

Abstract

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 PDIA3 C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3 C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3 C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3 C57Y 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.

Ablation of PDIA3 attenuates rheumatoid arthritis by restraining Th1 and Th17 polarization program

“…PDIA3 is known as a member of PDI family and exhibits redox regulation and protein disulfide isomerase activity (26). Interestingly, PDIA3 is expressed in various subcellular compartments where it exerts diverse biological functions (22,35,40).…”

“…There is also evidence that PDIA3 could translocate to the nucleus and boost STAT3 transcriptional activity (30,31). The pathophysiological functions of PDIA3 have been investigated in several cell types, including neuronal cells, chondrocytes and tumor cells (22,32,33), but its immune regulatory roles are less appreciated (34,35).…”

“…Endoplasmic reticulum (ER)-localized PDIA3 participates in the unfolded protein response (UPR) by regulating the correct folding and quality control of newly synthesized glycoproteins through the interaction with calnexin (CNX) and calreticulin (CRT) (22,23). Indeed, our previous work showed that SUMOylation of PDIA3 exacerbates proinsulin misfolding and ER stress in islet β cells (24).…”

The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment

“…Neuronal migration ASD, ID Desai et al, 1988;Whangbo and Kenyon, 1999;Turano et al, 2002;Wilkinson and Gilbert, 2004;Ellgaard and Ruddock, 2005;Fatemi et al, 2005;Iossifov et al, 2014;Wang et al, 2014;Parakh and Atkin, 2015;Lammert and Howell, 2016;Perri et al, 2016;Zeeshan et al, 2016;Lammert et al, 2017;Martin et al, 2018;Torpe et al, 2019;Bilches Medinas et al, 2022 Sigma…”

“…Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems ( Martin et al, 2018 ). Bilches et al conducted clinical and genetic studies on large close relatives with ID ( Bilches Medinas et al, 2022 ). These researchers isolated a homozygous mutant of PDIA3, c.170G > A (p. Cys57Tyr or C57Y), from the genes of clinical patients with ID and determined that this disease was associated with PDIA3.…”