EROS is required for phagocyte NADPH oxidase function in humans and its deficiency causes Chronic Granulomatous Disease

Abstract 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. We now show that the function of EROS is conserved in human cells and describe a case of CGD secondary to a homozygous EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of EROS in human immunity and describes a novel cause of CGD. Clinical Implications Chronic granulomatous disease is caused by an inability to make reactive oxygen species via the phagocyte NADPH oxidase. Mutations in C17ORF62/EROS, which controls gp91 phox - p22 phox abundance, are a novel cause of chronic granulomatous disease. Key Messages The murine gene, Eros , is known to regulate abundance of gp91 phox -p22 phox heterodimer and Eros deficient mice are susceptible to infection We show that the function of EROS is conserved in human cells and that a homozygous mutation in EROS causes chronic granulomatous disease