An in-frame triplet deletion within the gp91-phox gene in an adult X-linked chronic granulomatous disease patient with residual NADPH-oxidase activity

2009 ◽  
Vol 58 (2) ◽  
pp. 78-85 ◽  
Author(s):  
V. Jendrossek ◽  
A. Ritzel ◽  
B. Neubauer ◽  
S. Heyden ◽  
M. Gahr
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Disease Patient ◽  
Granulomatous Disease ◽  
Chronic Granulomatous Disease Patient ◽  
Nadph Oxidase Activity

Deficiency of NADPH oxidase activity in chronic granulomatous disease

1977 ◽  
Vol 90 (2) ◽  
pp. 213-217 ◽  
Author(s):  
Linda C. McPhail ◽  
Lawrence R. DeChatelet ◽  
Pamela S. Shirley ◽  
Catherine Wilfert ◽  
Richard B. Johnston ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity

scholarly journals Late-Onset of Chronic Granulomatous Disease Revealed By Paecilomyces Lilacinus Cutaneous Infection

2021 ◽  
Author(s):  
Clément Lemaigre ◽  
Felipe Suarez ◽  
Jean-Philippe Martellosio ◽  
Cindy Barbarin ◽  
Kevin Brunet ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Late Onset ◽  
Asymptomatic Carrier ◽  
Clinical Manifestations ◽  
Female Carrier ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity ◽  
Inherited Immunodeficiency

Abstract Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus, Paecylomyces lilacinus as the first manifestation of CGD. Dihydrorhodamin 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis of undetermined potential (CHIP) could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

scholarly journals Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1558-1562 ◽  
Author(s):  
RC Woodman ◽  
RW Erickson ◽  
J Rae ◽  
HS Jaffe ◽  
JT Curnutte
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Interferon Gamma ◽  
Oxidase Activity ◽  
Small Subset ◽  
Variant Form ◽  
Granulomatous Disease ◽  
Recombinant Interferon ◽  
Nadph Oxidase Activity ◽  
O2 Production

Recombinant interferon-gamma (rIFN-gamma) therapy has become an effective form of prophylaxis for patients with chronic granulomatous disease (CGD). Preliminary studies with CGD suggested that rIFN-gamma treatment enhanced phagocyte oxidase activity and increased superoxide (O2-) production. We evaluated several aspects of neutrophil NADPH oxidase activity in 19 CGD patients (representing all four known types of CGD) receiving prolonged rIFN-gamma therapy (6 to 27 months). In contrast to earlier studies, we failed to detect any improvement in neutrophil NADPH oxidase activity in 18 of the 19 CGD patients as determined by (1) intact cell O2- production (continuous assay), (2) nitroblue tetrazolium (NBT) staining, (3) cytochrome b558 spectroscopy, and (4) activity levels of cytosol and membrane oxidase components using a cell-free activation system. One patient with a variant form of X-linked CGD had a transient increase in neutrophil O2- production following 3 months of rIFN-gamma therapy. However, this was not sustained, and was not associated with any change in cytochrome b levels. In some patients, rIFN-gamma therapy was associated with the appearance of a small subset of circulating monocytes (1% to 20%) that were NBT-positive. Although the functional significance of this monocyte subpopulation needs to be determined, these results suggest that one possible mechanism by which rIFN-gamma may benefit CGD patients is by partially correcting the respiratory burst defect in a subset of monocytes. We conclude that the clinical benefit of prolonged rIFN-gamma therapy in the vast majority of CGD patients is not due to enhanced neutrophil NADPH oxidase activity. The mechanism of action of rIFN-gamma in most CGD patients remains unknown.

Long-Term Correction of Phagocyte NADPH Oxidase Activity by Retroviral-Mediated Gene Transfer in Murine X-Linked Chronic Granulomatous Disease

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 914-922 ◽  
Author(s):  
Mary C. Dinauer ◽  
Ling Lin Li ◽  
Helga Björgvinsdóttir ◽  
Chunjin Ding ◽  
Nancy Pech
Keyword(s):  
Gene Transfer ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Transplant Recipients ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Nadph Oxidase Activity

Chronic granulomatous disease (CGD) is an inherited deficiency of the superoxide-generating phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in recurrent, severe bacterial and fungal infections. The X-linked form of this disorder (X-CGD) results from mutations in the X-linked gene for gp91phox, the larger subunit of the oxidase flavocytochrome b558. In this study, we used a murine model of X-CGD to examine the long-term function of retroviral vectors for expression of gp91phox based on the murine stem cell virus (MSCV) backbone. NADPH oxidase activity was reconstituted in neutrophils and macrophages for up to 18 to 24 months posttransplantation of transduced X-CGD bone marrow into lethally irradiated syngeneic X-CGD mice. Southern blot analysis and secondary transplant data showed proviral integration in multilineage repopulating cells. Although relatively small amounts of recombinant gp91phox (approximately 5% to 10% of wild-type levels) were detected in neutrophils after retroviral-mediated gene transfer, superoxide-generating activity was approximately 20% to 25% of wild-type mouse neutrophils. Expression of gp91phox is normally restricted to mature phagocytes. No obvious toxicity was observed in other hematopoietic lineages in transplant recipients, and provirus-marked cells were capable of reconstituting secondary transplant recipients, who also exhibited NADPH oxidase–positive neutrophils. MSCV-based vectors for long-term expression of gp91phox may be useful for gene therapy of human CGD targeted at hematopoietic stem cells.

scholarly journals Late Onset of Chronic Granulomatous Disease Revealed by Paecilomyces lilacinus Cutaneous Infection

2021 ◽  
Author(s):  
Clément Lemaigre ◽  
Felipe Suarez ◽  
Jean-Philippe Martellosio ◽  
Cindy Barbarin ◽  
Kévin Brunet ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Late Onset ◽  
Asymptomatic Carrier ◽  
Clinical Manifestations ◽  
Paecilomyces Lilacinus ◽  
Female Carrier ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity

AbstractChronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X-inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus Paecilomyces lilacinus as the first manifestation of CGD. Dihydrorhodamine 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

Analysis of a p67phoxΔ401 Mutant Identified in Chronic Granulomatous Disease: Deletion of C-Terminal SH3 Binding Site for p47phox Still Supports NADPH Oxidase Activity in Cosphox Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2381-2381 ◽  
Author(s):  
A. A. Arias ◽  
J. D. Matute ◽  
P. J. Patino ◽  
M. C. Dinauer
Keyword(s):  
Functional Analysis ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Binding Site ◽  
Plasmid Dna ◽  
Oxidase Activity ◽  
Fold Increase ◽  
Sh3 Domain ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity

Abstract The phagocyte NADPH oxidase plays an essential role in host defense through the production of reactive oxygen species. Oxidase activation occurs via assembly of cytosolic p47phox, p67phox, p40phox and Rac with the membrane flavocytochrome b558. This work presents the functional analysis of a mutant p67phox identified in two unrelated patients affected with chronic granulomatous disease (CGD), a 5 nucleotide deletion in exon 13 that generates a premature stop codon at amino acid position 401. The p67phox-Δ401 (p67-d401) protein, which lacks the wild type (WT) C-terminal residues 398–526, has a truncated PB1 domain while the C-SH3 domain is absent. In neutrophils and EBV-B lymphocytes derived from a patient with this mutant, the protein was not detected and RNA appears to be unstable (Patino et al. 1999). This mutant was transiently expressed in COS7 cells that also expressed gp91phox, p22phox, and p47phox (COS91-22-47 cells) or the first two of these (COS91-22), from stable transgenes. The p67-d401 protein was expressed at lower levels (~38%) compared to p67- WT when the same amount of plasmid DNA was used for transfection, which was consistently observed over a three fold range of plasmid DNA; this suggests instability of the mRNA or protein. When normalized for protein expression, NADPH oxidase activity in cells expressing p67-d401 was similar to those expressing p67-WT in response to PMA and 3 times better in response to arachidonic acid (AA). Co-expression of p47phox was necessary for p67-d401 to support O2- production in response to AA and PMA. Co-expression of p40phox did not affect either expression levels of p67-WT or p67-d401 or NADPH oxidase activity. Very little p67-WT was detected in membranes of transfected resting COS91-22-47 cells, with some membrane translocation observed following stimulation with PMA or AA, as expected. Interestingly, a significant amount of p67-d401 was detected in membranes and very little in the cytosol of resting COS91-22-47 cells transfected with this mutant, similar to C-terminal truncation mutants studied by de Mendez and colleagues (de Mendez et al 1994, de Mendez et al 1996). Upon activation with AA or PMA, a ~1.5 fold increase in p67-d401 and a ~ 1.6 fold increase in p47phox associated with the membrane fraction was observed in COS91-22-47 cells transfected with p67-d401. Finally, transiently transfected p67-d401 co-immunoprecipitated with p47phox both in resting and stimulated COS91-22-47 cells. This indicates that the carboxyl terminal SH3 domain of p67phox is not the only site of interaction between p67phox and p47phox, and suggests that a second binding site exists. In conclusion, the COSphox system represents a transfectable whole cell model for functional analysis of mutant phox proteins with reduced stability in neutrophils. It is likely that over expression of the p67-d401 cDNA in this system permits detectable expression of recombinant p67-d401. The unusual properties of the p67-d401 mutant, with spontaneous membrane translocation as well as ability to interact with p47phox in the absence of the C-terminal p67phox SH3 domain may provide further insight into the multiplicity of interactions between each of the oxidase subunits and their relation with the Rac and the cytochrome b558.

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