Autosomal recessive chronic granulomatous disease caused by novel mutations in NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

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Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Blood ◽

10.1182/blood-2004-02-0675 ◽

2005 ◽

Vol 105 (1) ◽

pp. 61-66 ◽

Cited By ~ 58

Author(s):

Baruch Wolach ◽

Yitshak Scharf ◽

Ronit Gavrieli ◽

Martin de Boer ◽

Dirk Roos

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

X Chromosome ◽

Clinical Symptoms ◽

Novel Mutation ◽

Late Presentation ◽

Granulomatous Disease ◽

Phagocyte Nadph Oxidase ◽

Mucosal Cells ◽

General Defect

Abstract Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91phox, a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG[90-92] → GGT), predicting Tyr30Arg31 → stop, Val in gp91phox, who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her X-chromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow.

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A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Blood ◽

10.1182/blood-2009-07-231498 ◽

2009 ◽

Vol 114 (15) ◽

pp. 3309-3315 ◽

Cited By ~ 287

Author(s):

Juan D. Matute ◽

Andres A. Arias ◽

Nicola A. M. Wright ◽

Iwona Wrobel ◽

Christopher C. M. Waterhouse ◽

...

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Oxidase Activity ◽

Autosomal Recessive ◽

Premature Stop Codon ◽

Superoxide Production ◽

Human Neutrophils ◽

Granulomatous Disease ◽

Recessive Mutations ◽

Px Domain

Abstract Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91phox and p22phox, which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47phox and p67phox. A fifth subunit, p40phox, plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40phox, in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40phoxR105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40phox-deficient granulocytes, with premature loss of p40phoxR105Q from phagosomes. Thus, p40phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.

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Six differentCYBAmutations including three novel mutations in ten families from Turkey, resulting in autosomal recessive chronic granulomatous disease

European Journal of Clinical Investigation ◽

10.1111/j.1365-2362.2009.02093.x ◽

2009 ◽

Vol 39 (4) ◽

pp. 311-319 ◽

Cited By ~ 23

Author(s):

M. Y. Köker ◽

K. van Leeuwen ◽

M. de Boer ◽

F. Çelmeli ◽

A. Metin ◽

...

Keyword(s):

Chronic Granulomatous Disease ◽

Autosomal Recessive ◽

Granulomatous Disease ◽

Novel Mutations

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Molecular Characterization of Autosomal Recessive Chronic Granulomatous Disease Caused by a Defect of the Nicotinamide Adenine Dinucleotide Phosphate (Reduced Form) Oxidase Component p67-phox

Blood ◽

10.1182/blood.v94.7.2505.419k10_2505_2514 ◽

1999 ◽

Vol 94 (7) ◽

pp. 2505-2514 ◽

Cited By ~ 39

Author(s):

Pablo J. Patiño ◽

Julie Rae ◽

Deborah Noack ◽

Rich Erickson ◽

Jiabing Ding ◽

...

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Molecular Characterization ◽

Nicotinamide Adenine Dinucleotide ◽

Autosomal Recessive ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Splice Mutation ◽

Reduced Form ◽

Granulomatous Disease

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytes in which defective production of microbicidal oxidants leads to severe recurrent infections. CGD is caused by mutations in any of 4 genes encoding components of nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) oxidase, the multisubunit enzyme that produces the precursor of these oxidants, superoxide. Approximately 5% of CGD patients have an autosomal recessive form of disease caused by a severe deficiency of p67-phox, a 526-amino acid subunit of the oxidase that appears to regulate electron transport within the enzyme. Here we report the biochemical and molecular characterization of 6 unrelated kindreds with p67-phox deficiency. These studies show that, as in gp91-phox and p22-phox deficiencies, the p67-phox CGD patients show a high degree of heterogeneity in the genetic defects that underlie their disease. Five different mutant alleles were identified: (1) a nonsense mutation in exon 4 (C304 → T); (2) a 5-nucleotide (nt) deletion in exon 13 (nts 1169-1173); (3) a splice mutation in the first nucleotide of intron 4 (G → A); (4) a deletion of 1 nt in exon 9 (A728); and (5) a 9-nt in-frame deletion in exon 2 (nts 55-63). The splice mutation was seen in 3 unrelated kindreds, while the 5-nt deletion was seen in 2 apparently unrelated families (both of Palestinian origin). Homozygosity was present in 4 of the kindreds, 2 of which had consanguineous parentage. In the isolated neutrophils of each of the affected patients in the 6 kindreds, there was no measurable respiratory burst activity and no p67-phox protein detected by immunoblot analysis. The level of 67-phox mRNA was less than 10% of normal in the mononuclear leukocytes from 3 of the 4 patients analyzed by Northern blot studies. Thus, this heterogeneous group of mutations in p67-phox all lead to marked instability of mRNA or protein (or both) that results in the complete loss of NADPH oxidase activity.

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