Genetic disorders coupled to ROS deficiency

Abstract

Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as 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 genetic variants ( CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/ DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure–function studies that will aid in predicting functional defects of clinical variants.

Graphical abstract

Highlights

• •

  Deficiency in reactive oxygen species is often caused by NADPH oxidase variants.

• •

  Overview of chronic granulomatous disease and alterations in the Nox2 complex.

• •

  CGD iPS cells as promising novel tools.

• •

  Risk for inflammatory bowel disease by Nox2 complex, Nox1 and Duox2 mutations.

• •

  Loss-of-function variants in DUOX2 and DUOXA2 trigger congenital hypothyroidism.