EROS/CYBC1 mutations: Decreased NADPH oxidase function and chronic granulomatous disease

Abstract

Short Summary The phagocyte respiratory burst is mediated by the phagocyte NADPH oxidase, a multi-protein subunit complex that facilitates production of reactive oxygen species and which is essential for host defence. Monogenic deficiency of individual subunits leads to chronic granulomatous disease (CGD), which is characterized by an inability to make reactive oxygen species, leading to severe opportunistic infections and auto-inflammation. However, not all cases of CGD are due to mutations in previously identified subunits. We recently showed that Eros, a novel and highly conserved ER-resident transmembrane protein, is essential for the phagocyte respiratory burst in mice because it is required for expression of gp91 phox -p22 phox heterodimer, which are the membrane bound components of the phagocyte NADPH oxidase. Eros has a human orthologue, CYBC1 / EROS . We now show that the function of CYBC1/EROS is conserved in human cells and describe a case of CGD secondary to a homozygous CYBC1/EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of CYBC1/EROS in human immunity and describes a novel cause of CGD.