Characterization of missense mutations in the NADPH oxidase partner p22^phox in the A22° subtype of chronic granulomatous disease

Abstract Defective superoxide production by NADPH oxidase 2 (Nox2) in phagocyte cells results in the development of chronic granulomatous disease (CGD), a hereditary disease characterized by recurrent and life‐threatening infections. The partner protein p22 phox is a membrane‐spanning protein which forms a stable heterodimer with Nox2 in the endoplasmic reticulum. This interaction ensures the stability of each protein and their accurate trafficking to the cell membrane. The present paper describes the characterization of p22 phox missense mutations that were identified in a patient with CGD who presented with undetectable levels of p22 phox . Using a reconstitution system, it was found that p22 phox expression decreased when R90Q, A117E, S118R, A124S, A124V, A125T, or E129K mutations were introduced, suggesting that these mutations destabilize the protein. In contrast, introducing an L105R mutation did not affect protein expression, but did inhibit p22 phox binding to Nox2. Thus, the missense mutations discussed here contribute to the development of CGD by either disrupting protein stability or by impairing the interaction between p22 phox and Nox2.