ROS DEFICIENCY AS DISEASE RISK

Abstract

Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte NOX2 oxidase function due to inactivating genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) cause chronic granulomatous disease (CGD), an inherited immune disorder. Reduced superoxide generation by the NOX2 complex constitutes a risk factor for developing very early onset inflammatory bowel disease (VEOIBD). VEOIBD has also been linked to NOX1 and DUOX2 variants, both expressed in the colon epithelium, thereby strengthening the notion that sufficient ROS generation is essential for gut health. Loss-of- function variants in the genes encoding for the DUOX2/DUOXA2 complex lead to permanent or transient hypothyroidism, although it still remains unknown what determines the clinical manifestations when DUOX2 activity is reduced. I will give an overview of developments in NOX/DUOX-deficiency disorders and combine them with insights gained from structure-function studies that will aid in predicting functional defects of clinical variants.