Chronic granulomatous disease (CGD) results from defects in the NADPH oxidase system which generates reactive oxygen species to kill pathogens. There are several forms of CGD involving defects in different components of the NOX2 system. The majority of CGD cases involve mutations in the CYBB gene encoding the gp91-phox subunit of cytochrome b558. Other forms involve mutations in other genes encoding subunits of the NOX2 complex. Individuals with deficiencies in NADPH production can also exhibit similar symptoms to CGD.
2. Chronic Granulomatous Disease
• Because of the need for NADPH in phagocytic cells, by the NADPH
oxidase (NOX) system, any defect in enzymes in this process can result in
impaired killing of infectious organisms. Humans express several
complexes of the NADPH oxidase family. The specific NOX system of
phagocytic cells is a multisubunit complex whose function is to generate
reactive oxygen species (ROS) as a means to destroy invading pathogens.
This particular NADPH oxidase system is referred to as NOX2.
• Chronic granulomatous disease (CGD) is a syndrome that results in
individuals harboring defects in the NOX2 form of the NADPH oxidase
system. The NOX2 system is a multisubunit enzyme complex preferentially
expressed in cells of the myeloid lineage. NADPH oxidase complexes are
composed of protein subunits that interact to form the functional enzyme
complex. The NOX2 system is designed to generate reactive oxygen
species (ROS), referred to as the oxidative burst, as a means to eliminate
invading microorganisms in macrophages and neutrophils.
3. Chronic Granulomatous Disease
• All NAPDH oxidase systems are multisubunit enzyme complexes. Two of the proteins of the
NOX2 complex are integral membrane proteins and they are identified as p22-PHOX
(p22phox; also known as the α-subunit) and gp91-PHOX (gp91phox; also known as the β-
subunit). The PHOX designation refers to phagocyte oxidase. These two subunits form a
large heterodimeric complex that is referred to as cytochrome b558 (cyt b558). Three of the
subunits of NADPH oxidase are regulatory subunits and these remain in the cytosol in the
unstimulated state. These regulatory subunits are identified as p40-PHOX, p47-PHOX, and
p67-PHOX. When cells are appropriately stimulated, the p47-PHOX subunit is
phosphorylated and the entire heterotrimeric complex migrates to the membrane where it
associates with the cyt b558 complex.
• Two additional proteins are involved in the function of NADPH oxidase systems and both
are members of the low molecular weight monomeric G-protein family. These G-proteins are
identified as RAC2 (RAC family small GTPase 2) and RAP1A (RAS-related protein 1A). The
formation of this membrane associated enzyme complex results in the generation of
superoxide anion which in turn is converted to hydrogen peroxide through the action of Cu-
Zn superoxide dismutase (SOD1). The generation of these ROS within the phagocytic
complexes of macrophages and neutrophils is the means by which these cells degrade
phagocytosed microorganisms.
4. Chronic Granulomatous Disease
• There are several forms of CGD involving defects in various
components of the NADPH oxidase 2 (NOX2) system. The
majority of patients (67%) with CGD harbor mutations in an X-
chromosome gene (CYBB) that encodes the β-subunit (gp91-
PHOX) of cytochrome b558. This form of the disorder is referred
to as cytochrome b-negative X-linked CGD.
• There is an autosomal recessive cytochrome b-negative form of
CGD due to defects in the α-subunit (p22-PHOX) of
cytochrome b558. The p22-PHOX protein is encoded by the
CYBA gene. Mutations in the CYBA gene account for
approximately 5% of CGD cases.
5. Chronic Granulomatous Disease
• There are also two autosomal recessive cytochrome b-positive forms of CGD
identified as cytochrome b-positive CGD type I and type II. The type I form
represents about 20% of all CGD cases and is caused by mutations in the
neutrophil cytosolic factor 1 (NCF1) gene, which encodes the p47-PHOX
protein. The type II form represents about 5% of all cases of CGD and is the
result of mutations in the NFC2 gene which encodes the p67-PHOX protein.
The p40-PHOX protein is encoded by the neutrophil cytosolic factor 4 (NCF4)
gene. Mutations in the NFC4 component of the NADPH oxidase system has
been reported in a single case of CGD.
• In addition to the NOX2 complexes that function in phagocytic cells there are
several additional NADPH oxidase systems that function in many other types
of cells. These complexes are referred to as NOX1, NOX3, NOX4, NOX5,
DUOX1 (dual oxidase 1), and DUOX2. The DUOX1 and DUOX2 members of
the NADPH oxidase family are involved in the generation of the the thyroid
hormones.
6. Chronic Granulomatous Disease
• Given the role of NADPH in the process of phagocytic killing it
should be clear that individuals with reduced ability to produce
NADPH (such as those with G6PD deficiencies) may also
manifest with symptoms that have similarities to those of
classically inherited forms of CGD.
