Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: NOX1

Red List (low evidence)

NOX1 is an X-linked gene encoding NADPH Oxidase 1, an enzyme highly expressed in the colonic epithelium. At the apical brush border, NOX1 constitutively generates reactive oxygen species (ROS) into the crypt lumen. This localized ROS production is a critical component of the intestinal epithelial barrier, mediating innate antimicrobial defense and regulating host-microbe interactions at the mucosal interface without playing a role in systemic phagocytic oxidative bursts.

Defects in NOX1 are associated with mucosal immune dysregulation and Very Early-Onset Inflammatory Bowel Disease (VEO-IBD). Hemizygous loss-of-function missense variants (e.g., p.N122H) have been identified in male patients presenting with severe, early-onset ulcerative colitis-like pathology and pancolitis. Functional analyses of patient-derived organoids and ex vivo colonic explants demonstrate that these variants profoundly abrogate epithelial ROS production, leading to impaired host resistance to enteric microbes and subsequent severe intestinal inflammation (Hayes et al., 2015; Schwerd et al., 2018).

Unlike defects in the phagocytic NADPH oxidase (CYBB/NOX2), which cause classical Chronic Granulomatous Disease with systemic susceptibility to infection, NOX1 deficiency specifically impairs the epithelial innate immune compartment. Furthermore, large cohort analyses suggest that NOX1 loss-of-function variants may not always present as a fully penetrant Mendelian disorder, but rather act as a high-impact genetic modifier that drastically lowers the threshold for VEO-IBD when combined with specific microbial or environmental triggers (Schwerd et al., 2018).
Sources: Literature

Created: 17 Jun 2026, 3 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Inflammatory bowel disease; IBD; VEOIBD

Publications

• 32064493
• 26301257
• 29091079