Molecular epidemiology of chronic granulomatous disease in a series of 80 kindreds: identification of 31 novel mutations

Abstract

Chronic granulomatous disease (CGD) results from constitutional inactivating mutations in the CYBB, NCF1, CYBA or NCF2 genes that encode subunits of phagocyte NADPH oxidase. We report the findings of molecular analysis of 80 kindred. In 75 unrelated male and 5 female probands, CGD was suspected on the basis of clinical symptoms, and biological samples were referred to our laboratory between 2000 and 2007. Seventy seven patients were found to have mutations in CYBB, NCF1, CYBA or NCF2 (52 different mutations including 31 mutations not previously reported). CYBB was the most frequently mutated gene (58 males and 3 females, 76%). In autosomal recessive forms of the disease, mutations were found in NCF1 (11 patients), NCF2 (3 patients) and CYBA (2 patients). We observed that significantly fewer females were affected by autosomal recessive CGD than expected (2 females/14 males; p=0.002), suggesting that female patients with CGD may be under diagnosed.

p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases

“…Thus PKCζ (Dang et al, 2001a), PKCβ (Dekker et al, 2000;Korchak et al, 2001), PKCδ (Bey et al, 2004;Brown et al, 2003;Cheng et al, 2007), PAK (Martyn et al, 2005), ERK1/2 (Dewas et al, 2000) and AKT (Chen et al, 2003) were shown to play a stimulatory role in fMLF-or PMA-induced NADPH oxidase activation. Proinflammatory cytokines such as GM-CSF and TNFα which do not activate NADPH oxidase but prime its activation in response to a secondary stimulus such as fMLF (El Benna et al, 2008), induce partial phosphorylation of p47phox on Ser345 by ERK1/2 or p38MAPK and promote NADPH oxidase assembly (Dang et al, 1999(Dang et al, , 2006Dewas et al, 2003). While phosphorylation of p47phox by PKC, PAK and AKT in neutrophils has a positive stimulatory effect on NADPH oxidase activation and pre-phosphorylation by p38MAPkinase and ERK1/2 results in the enhancement of this effect, some data have suggested that the phosphorylation of p47phox by PKA or CKII could have a negative inhibitory effect (Bengis-Garber et al, 1996;Park et al, 2001).…”

“…The most common pathogens encountered in CGD patients are gram-positive bacteria (Staphylococcus aureus), gram-negative bacteria (Salmonella, Pseudomonas cepacia, Serratia marcescens…) and fungi (Aspergillus, Candida albicans). Aspergillus species can cause intractable pneumonia and sometimes septicemia in CGD patients, and are a frequent cause of death (Meischl and Roos, 1998;Kannengiesser et al, 2008). CGD results from mutations in the NADPH oxidase component genes, namely the CYBB gene (Xp21) that encodes the gp91phox subunit, and the CYBA gene (16q24), the NCF1 gene (7q11) and the NCF2 gene (1q25) which encode p22phox, p47phox, p67phox, respectively.…”

“…CGD results from mutations in the NADPH oxidase component genes, namely the CYBB gene (Xp21) that encodes the gp91phox subunit, and the CYBA gene (16q24), the NCF1 gene (7q11) and the NCF2 gene (1q25) which encode p22phox, p47phox, p67phox, respectively. The most frequent form of CGD (approximately 70% of all cases) is the X-linked gp91phox-deficient form, followed by the autosomal form deficient in p47phox (approximately 25%) (Meischl and Roos, 1998;Kannengiesser et al, 2008). Less frequent forms are autosomal CGD deficient in p67phox (＜ 5%) and p22phox (＜ 5%) (Roos et al, 1996).…”

“…Although ROS production by NADPH oxidase plays a key role in host defenses against microbial pathogens, excessive ROS release can also damage bystander host tissues, thereby amplifying inflammatory reactions (Babior 1984(Babior , 2000El Benna et al, 2008). Increasing evidence suggests that NADPH oxidase is involved in inflammatory diseases such as rheumatoid arthritis.…”

“…The enzyme responsible for O 2 -production is the multicomponent NADPH oxidase or respiratory burst oxidase (Babior, 1999;El Benna et al, 2005). The phagocyte NADPH oxidase and ROS production play a key role in host defense against microbial pathogens as illustrated by a human genetic disorder called chronic granulomatous disease (CGD), which is associated with life-threatening bacterial and fungal infections and is characterized by an absence of ROS production due to a deficiency in one of the components of the NADPH oxidase (Meischl and Roos, 1998;Kannengiesser et al, 2008).…”