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.

A Novel c.554+5C>T Mutation in the DUOXA2 Gene Combined with p.R885Q Mutation in the DUOX2 Gene Causing Congenital Hypothyroidism

“…Defects in the DUOX2/DUOXA2 heterodimer lead to hypothyroidism and goiter. Since the first report in 2002 of DUOX2 mutations causing CH (10,11), over 40 mutations in the DUOX2 gene have been described correlated with CH, while only four mutations have been identified in the DUOXA2 gene (3,8,9,10). Thus far, our splice site mutation, as far as we know, is identified for the first time as being causative of CH.…”

“…The patients with DUOX2 or DUOXA2 mutation show a great genotype-phenotype variability (10,11). Maruo et al (3) firstly reported the p.R885Q mutation in the DUOX2 gene exhibiting transient hypothyroidism, which is not similar to our patient.…”

“…DUOXA2 is required for normal DUOX2 enzymatic activity. It has been identified that DUOXA2 is crucial for DUOX2 maturation, and genetic defects in DUOX2 cause CH and subclinical another important candidate gene for CH and SCH (3,4,8,9,10). …”

Oxidative Stress in Urolithiasis

“…These generated ROS are believed to be responsible for destroying the engulfed pathogens in the phagolysosome. Mutation in genes encoding for NADPH oxidase complexes resulting in insufficient ROS production that is a direct cause of chronic granulomatous disease (CGD) [92]. CGD is a rare inherited immune disorder caused from the inability of phagocytes to kill the ingested microbes, and its typical manifestation is frequently recurrent subcutaneous abscess formation together with hyperinflammation.…”

The physicochemical properties of membranes correlate with the NADPH oxidase activity

“…The superoxide anion is the precursor of the so-called Reactive Oxygen Species (ROS) which serve as microbicide weapons. The physiological importance of the phagocyte NADPH oxidase is evidenced by an immunodeficiency disease called chronic granulomatous disease (CGD), in which defective microorganism killing entails recurrent and severe infections (reviewed in [1]). Studies over the last decade revealed homologs of phagocyte NADPH oxidases forming the NOX family [2,3], which enlarged considerably the number of its physiological functions (inflammatory response, post-translational proteins processing, inter-and intra-cellular signaling, regulation of endothelial function, regulation of gene expression and cell differentiation…).…”