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

• DOI: 10.15252/embj.2020105531
• Publication Date: 2021-12-14T14:07:57Z
• Authors: Danilo Bilches Me...; Sajid Malik; Esra Yıldız‐Bölük...; Janina Borgonovo; Mirva J Saaranen; Hery Urra; Eduardo Pulgar; Muhammad Afzal; Darwin Contreras; Madison T Wright; Felipe Bodaleo; Gabriel Quiroz; Pablo Rozas; Sara Mumtaz; Rodrigo Díaz; Carlos Rozas; Felipe Cabral‐Mir...; Ricardo Piña; Vicente Valenzuela; Ozgun Uyan; Christopher Reardon; Ute Woehlbier; Robert H Brown; Miguel Sena‐Esteves; Christian Gonzale...; Bernardo Morales; Lars Plate; Lloyd W Ruddock; Miguel L Concha; Claudio Hetz; Aslıhan Tolun
• Keywords: Adult; Male; Integrins; actin cytoskeleton; Adolescent; Developmental Disabilities; Neuronal Outgrowth; Mutation, Missense; Endoplasmic Reticulum; Hippocampus; Mice; 03 medical and health sciences; Cell Adhesion; Animals; Humans; Child; Cells, Cultured; Cytoskeleton; 0303 health sciences; Neuronal Plasticity; cell adhesion; protein disulfide isomerase; Axons; Mice, Inbred C57BL; intellectual disability; integrins; Female

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.