Mutant PDIA3 causes neurodevelopmental impairment by disturbing endoplasmic reticulum proteostasis

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.