Genetic disorders coupled to ROS deficiency - PubMed (original) (raw)
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Genetic disorders coupled to ROS deficiency
Sharon O'Neill et al. Redox Biol. 2015 Dec.
Abstract
Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure-function studies that will aid in predicting functional defects of clinical variants.
Keywords: Chronic granulomatous disease; DUOX; Genetic disease; Hypothyroidism; Inflammatory bowel disease; NADPH oxidase; NOX; Reactive oxygen species (ROS).
Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
Figures
Graphical abstract
Fig. 1
Molecular basis of chronic granulomatous disease. CGD is caused by alterations in CYBB, CYBA, NCF1, NCF2 or NCF4 encoding Nox2, p22_phox_, p47_phox_, p67_phox_ and p40_phox_ respectively. The main genetic form is X-linked CGD representing about 70% of total cases. Three autosomal recessive CGD forms, AR-CGD470, AR-CGD670, and AR-CGD220, represent the rest of the cases described, the AR-CGD470 being the most frequent form (25% of cases). Only one NCF4 variant has been described up to now.
Fig. 2
Molecular mechanisms of NADPH oxidase complex activation. The NADPH oxidase complex of phagocytic cells is dissociated in resting phagocytes. Cytochome b_558 composed of Nox2 and p22_phox is localized in the plasma membrane and the cytosolic factors p47_phox_, p67_phox_ and p40_phox_ form a complex in the cytoplasm. The small GTP-binding protein Rac associates with Rho-GDI in its inactive GDP form. Upon activation, signaling events cause phosphorylations and conformational changes of the NADPH oxidase subunits leading to their assembly. Activated Rac-GTP translocates, anchors in the membrane and binds to the NADPH oxidase complex. The fully assembled NADPH oxidase complex is able to trigger electron transfer from NADPH to FAD and hemes to reduce molecular oxygen into superoxide.
Fig. 3
Localization of X+- and X−-CGD mutations in Nox2. The N-terminal part of the Nox2 protein is embedded in the plasma membrane and is structured into six α-helices, two cytosolic loops (B, D), and three external loops (A, C, E), and contains two non-identical hemes coordinated by four histidine (H) residues located in the third and fifth transmembrane helices. Nox2 is glycosylated on asparagines in C and E loop (ϒ). In the cytosolic “dehydrogenase domain” of Nox2, the FAD/NADPH-binding domains are illustrated as gray clouds. Variants causing X+-CGD are preferentially located in the C-terminal part of Nox2 (A). Green and pink circles and squares correspond to X+-CGD missense variants . Pink circles are variants studied in the PLB-985 cell model [57,62,63,65–67,247]. Blue and red circles, squares and triangles correspond to X−-CGD missense variants, deletions or duplications respectively . Red circles are additional variants studied in the PLB-985 cell model . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Phenotypic and functional characterization of neutrophils and macrophages derived from WT and CGD iPSCs. (A) MGG staining showing the characteristic morphology of neutrophils (upper panel, scale bar 10 µm) and macrophages (lower panel, scale bar 20 µm). (B) Electron microscopy shows the presence of cytoplasmic granules in neutrophils and vacuoles in macrophages (scale bar 2 µm). (C) NBT reduction assay on opsonized latex bead-activated WT or CGD iPSC-derived neutrophils (upper panel, scale bar 10 µm) and macrophages (lower panel, scale bar 20 µm). ROS-mediated NBT reduction is shown as blue formazan precipitates in WT neutrophils and macrophages (black arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Missense mutations in cytosolic Nox2 complex components associated with VEOIBD without leading to CGD. NADPH oxidase activation triggers multiple phosphorylations and structural rearrangements, exposing domains masked by intramolecular interactions and permitting novel interactions required for assembly of the oxidase complex. Constitutive interactions are indicated by blue arrows, stimulus-induced interactions by purple arrows. Location of variants indicated in red. For domain explanation see text except: AIR (autoinhibitory region), PRR (proline-rich region), AD (activation domain). Adapted from . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 6
NOX1 variants identified as VEOIBD risk factor. Two functionally altered NOX1 variants were recently identified in VEOIBD patients, one located upstream of the first FAD binding domain, while the other is located within the second FAD domain (indicated by black dots). p22_phox_ is represented as a 4 transmembrane (TM) domain protein, although models with 2 or 3 TM exist.
Fig. 7
DUOX2 variants associated with hypothyroidism or VEOIBD. Mutations in Duox2 and DuoxA2 are prevalent in congenital hypothyroidism (CH). To date, over 40 DUOX2 variants and 4 DUOXA2 variants have been characterized. Duox2 CH mutations span the entire protein and are depicted as red dots, while DuoxA2 CH mutations are shown in green. Two DUOX2 variants, recently identified as risk factors for VEOIBD, are indicated by black dots. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
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