Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease.

BACKGROUND: S AND AIM: The gastrointestinal epithelium plays a crucial role in maintaining homeostasis with the gut microbiome. Mucins are essential for intestinal barrier function and serve as a scaffold for antimicrobial factors. MUC2 is the major intestinal gel-forming mucin produced predominantly by goblet cells. Goblet cells express AGR2, a protein disulfide isomerase (PDI) that is crucial for proper processing of gel-forming mucins. Here, we investigated two siblings who presented with severe infantile onset inflammatory bowel disease. METHODS: We performed whole genome sequencing to identify candidate variants. We quantified goblet cell numbers using H&E histology and investigated the expression of gel-forming mucins, stress markers, and goblet cell markers using immunohistochemistry. AGR2-MUC2 binding was evaluated using co-immunoprecipitation. Endoplasmic reticulum (ER) stress regulatory function of mutant AGR2 was examined by expression studies in HEK293T using tunicamycin to induce ER stress. RESULTS: Both affected siblings were homozygous for a missense variant in AGR2. Patient biopsies showed reduced goblet cells, depletion of MUC2, MUC5AC, and MUC6, upregulation of AGR2, and elevated ER stress. The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. CONCLUSIONS: Phenotype-genotype segregation, functional experiments, and the striking similarity of the human phenotype to the AGR2-/- mouse models suggest that the AGR2 missense variant is pathogenic. The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile onset IBD.