scholarly journals A new mutation in exon 12 of the gp91-phox gene leading to cytochrome b- positive X-linked chronic granulomatous disease

Blood ◽  
1995 ◽  
Vol 85 (11) ◽  
pp. 3274-3277 ◽  
Author(s):  
H Azuma ◽  
H Oomi ◽  
K Sasaki ◽  
I Kawabata ◽  
T Sakaino ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Cytochrome B ◽  
Dna Analysis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Granulomatous Disease ◽  
New Mutation ◽  
Nadph Oxidase Complex ◽  
Polymerase Chain ◽  
O2 Production ◽  
Complete Formation

We have previously reported a patient with cytochrome b-positive X-linked chronic granulomatous disease. Although the O2-production of neutrophils from the patient was completely defective, we presented data suggesting that the patient's cytochrome b was present at a normal level and possibly had normal spectroscopic features. Thus, to look for a mutation in the cytochrome b heavy chain (gp91-phox) gene, DNA analysis of gp91-phox cDNA derived from this patient was performed. As a result, we found that five nucleotides (1521 through 1525) within exon 12 were deleted, and a new sequence of eight nucleotides was inserted. This mutation converted Gln507-Lys508-Thr509 into His-Ile-Trp-Ala. Mismatched polymerase chain reaction showed that the mother has both wild and mutated alleles, confirming that this case was transmitted in an X-linked fashion. This mutation is different from those previously reported by others. The translocation of p47-phox and p67-phox to the membrane fraction occurred, indicating the complete formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. We conclude that this case suggests that the structure encoded on exon 12 of gp91-phox is important for electron transfer.

scholarly journals p22-phox-deficient chronic granulomatous disease: reconstitution by retrovirus-mediated expression and identification of a biosynthetic intermediate of gp91-phox

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2767-2775 ◽  
Author(s):  
CD Porter ◽  
MH Parkar ◽  
AJ Verhoeven ◽  
RJ Levinsky ◽  
MK Collins ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Cell Lines ◽  
Cytochrome B ◽  
Function Analysis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Side Chains ◽  
In Vitro Mutagenesis ◽  
Granulomatous Disease ◽  
P22 Phox

Chronic granulomatous disease (CGD) results from defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, central to which is the membrane-bound cytochrome b-245. The cytochrome is composed of two protein subunits, the larger (gp91-phox) being deficient in X-linked CGD. In this study, we have analyzed expression of the cytochrome subunits in B-cell lines from two autosomal CGD patients for whom the disease is caused by deficiency of p22-phox, the smaller subunit. We report the presence of a 65-kD precursor of gp91- phox in the membrane fraction of both p22-phox-deficient cell lines, corresponding to the core protein with N-linked carbohydrate side chains in the high mannose form. Expression of p22-phox in these cells resulted in functional correction of NADPH oxidase. In addition, gp91- phox in the reconstituted cells was processed to its terminally glycosylated form. These data suggest that the association of the 65-kD gp91-phox precursor with p22-phox is a prerequisite for processing of the carbohydrate side chains to the complex form in the Golgi. The detection of this precursor will enable characterization of mutations disrupting the subunit interaction (either naturally occurring or derived by in vitro mutagenesis) and so aid in structure-function analysis of cytochrome b-245. Reconstitution of p22-phox-deficient cells shows the potential of gene therapy for this autosomal form of CGD.

scholarly journals Undiagnosed Chronic Granulomatous Disease,Burkholderia cepacia complexPneumonia, and Acquired Hemophagocytic Lymphohistiocytosis: A Deadly Association

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Maxime Maignan ◽  
Colin Verdant ◽  
Guillaume F. Bouvet ◽  
Michael Van Spall ◽  
Yves Berthiaume
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Burkholderia Cepacia ◽  
Autosomal Recessive ◽  
Dna Analysis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Multiple Organ ◽  
Burkholderia Cepacia Complex ◽  
Granulomatous Disease

Background. Chronic granulomatous disease is a rare inherited disorder of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The clinical course of the disease is marked by recurrent infections, includingBurkholderia cepacia complexinfection.Case Report. Here we report the case of a 21-year-old male hospitalized for aBurkholderia cepacia complexpneumonia. Despite the broad spectrum antibiotic treatment, fever continued and patient’s condition worsened. Anemia and thrombocytopenia developed together with hypofibrinogenemia. The patient died of multiple organ dysfunction 17 days after his admission. Autopsy revealed hemophagocytosis, suggesting the diagnosis of acquired hemophagocytic lymphohistiocytosis. DNA analysis showed a deletion in the p47phox gene, confirming the diagnosis of autosomal recessive chronic granulomatous disease.Discussion. In addition to chronic granulomatous disease, recent findings have demonstrated thatBurkholderia cepacia complexcan decrease activity of the NADPH oxidase. Interestingly, hemophagocytic lymphohistiocytosis is characterized by an impaired function of the T-cell mediated inflammation which is partly regulated by the NADPH oxidase. Physicians should therefore pay particular attention to this deadly association.

scholarly journals Somatic Triple Mosaicism in a Carrier of X-Linked Chronic Granulomatous Disease

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 252-257 ◽  
Author(s):  
Martin de Boer ◽  
Egbert Bakker ◽  
Stefaan Van Lierde ◽  
Dirk Roos
Keyword(s):  
Chronic Granulomatous Disease ◽  
Genomic Dna ◽  
Gene Sequence ◽  
Somatic Mosaicism ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Granulomatous Disease ◽  
Gene Sequence Analysis ◽  
Triple X Syndrome ◽  
Cybb Gene ◽  
Polymerase Chain

Abstract The X-linked form of chronic granulomatous disease (CGD) is caused by mutations in the CYBB gene, which encodes the 91-kD subunit of the flavocytochrome b558, a component of the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytic leukocytes. Mutations in this gene are very heterogeneous and often unique for one family. Here we report on a family with two patients (brothers), one with a 3-kb deletion comprising exon 5 and the other with a 3.5-kb deletion comprising exons 6 and 7 of the CYBB gene. Sequence analysis of polymerase chain reaction (PCR)-amplified genomic DNA proved these deletions to be overlapping for 35 bp. Analysis by restriction fragment length polymorphism of genomic DNA from the mother's leukocytes showed her to be a carrier of both deletions in addition to the normal CYBB sequence. This triple somatic mosaicism was confirmed with PCR-amplified genomic and complementary DNA. The presence of the normal CYBB gene in the mother was also proven by the finding of normal superoxide-generating neutrophils in addition to cells lacking this ability. Triple X syndrome was excluded. These findings suggest that the mutations are the result of an event in early embryogenesis of the mother, possibly involving a mechanism like sister chromatid exchange.

scholarly journals p22-phox-deficient chronic granulomatous disease: reconstitution by retrovirus-mediated expression and identification of a biosynthetic intermediate of gp91-phox

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2767-2775 ◽  
Author(s):  
CD Porter ◽  
MH Parkar ◽  
AJ Verhoeven ◽  
RJ Levinsky ◽  
MK Collins ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Cell Lines ◽  
Cytochrome B ◽  
Function Analysis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Side Chains ◽  
In Vitro Mutagenesis ◽  
Granulomatous Disease ◽  
P22 Phox

Abstract Chronic granulomatous disease (CGD) results from defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, central to which is the membrane-bound cytochrome b-245. The cytochrome is composed of two protein subunits, the larger (gp91-phox) being deficient in X-linked CGD. In this study, we have analyzed expression of the cytochrome subunits in B-cell lines from two autosomal CGD patients for whom the disease is caused by deficiency of p22-phox, the smaller subunit. We report the presence of a 65-kD precursor of gp91- phox in the membrane fraction of both p22-phox-deficient cell lines, corresponding to the core protein with N-linked carbohydrate side chains in the high mannose form. Expression of p22-phox in these cells resulted in functional correction of NADPH oxidase. In addition, gp91- phox in the reconstituted cells was processed to its terminally glycosylated form. These data suggest that the association of the 65-kD gp91-phox precursor with p22-phox is a prerequisite for processing of the carbohydrate side chains to the complex form in the Golgi. The detection of this precursor will enable characterization of mutations disrupting the subunit interaction (either naturally occurring or derived by in vitro mutagenesis) and so aid in structure-function analysis of cytochrome b-245. Reconstitution of p22-phox-deficient cells shows the potential of gene therapy for this autosomal form of CGD.

scholarly journals Second Report of Chronic Granulomatous Disease in Jordan: Clinical and Genetic Description of 31 Patients From 21 Different Families, Including Families From Lybia and Iraq

2021 ◽  
Vol 12 ◽  
Author(s):  
Faris Ghalib Bakri ◽  
Michelle Mollin ◽  
Sylvain Beaumel ◽  
Bénédicte Vigne ◽  
Nathalie Roux-Buisson ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Autosomal Recessive ◽  
Common Ancestor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Clinical History ◽  
Granulomatous Disease ◽  
Molecular Features ◽  
Immunodeficiency Disorder ◽  
Nadph Oxidase Complex ◽  
Prevalent Form

Chronic granulomatous Disease (CGD) is a rare innate immunodeficiency disorder caused by mutations in one of the six genes (CYBA, CYBB, NCF1, NCF2, NCF4, and CYBC1/EROS) encoding the superoxide-producing nicotinamide adenine dinucleotide phosphate (NADPH)—oxidase complex in phagocytes. In the Western population, the most prevalent form of CGD (about two-thirds of all cases) is the X-linked form (X-CGD) caused by mutations in CYBB. The autosomal recessive forms (AR-CGD), due to mutations in the other genes, collectively account for the remaining one-third of CGD cases. We investigated the clinical and molecular features of 22 Jordanian, 7 Libyan, and 2 Iraqi CGD patients from 21 different families. In addition, 11 sibling patients from these families were suspected to have been died from CGD as suggested by their familial and clinical history. All patients except 9 were children of consanguineous parents. Most of the patients suffered from AR-CGD, with mutations in CYBA, NCF1, and NCF2, encoding p22phox, p47phox, and p67phox proteins, respectively. AR-CGD was the most frequent form, in Jordan probably because consanguineous marriages are common in this country. Only one patient from non-consanguineous parents suffered from an X910 CGD subtype (0 indicates no protein expression). AR670 CGD and AR220 CGD appeared to be the most frequently found sub-types but also the most severe clinical forms compared to AR470 CGD. As a geographical clustering of 11 patients from eight Jordanian families exhibited the c.1171_1175delAAGCT mutation in NCF2, segregation analysis with nine polymorphic markers overlapping NCF2 indicates that a common ancestor has arisen ~1,075 years ago.

scholarly journals Somatic Triple Mosaicism in a Carrier of X-Linked Chronic Granulomatous Disease

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 252-257
Author(s):  
Martin de Boer ◽  
Egbert Bakker ◽  
Stefaan Van Lierde ◽  
Dirk Roos
Keyword(s):  
Chronic Granulomatous Disease ◽  
Genomic Dna ◽  
Gene Sequence ◽  
Somatic Mosaicism ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Granulomatous Disease ◽  
Gene Sequence Analysis ◽  
Triple X Syndrome ◽  
Cybb Gene ◽  
Polymerase Chain

The X-linked form of chronic granulomatous disease (CGD) is caused by mutations in the CYBB gene, which encodes the 91-kD subunit of the flavocytochrome b558, a component of the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytic leukocytes. Mutations in this gene are very heterogeneous and often unique for one family. Here we report on a family with two patients (brothers), one with a 3-kb deletion comprising exon 5 and the other with a 3.5-kb deletion comprising exons 6 and 7 of the CYBB gene. Sequence analysis of polymerase chain reaction (PCR)-amplified genomic DNA proved these deletions to be overlapping for 35 bp. Analysis by restriction fragment length polymorphism of genomic DNA from the mother's leukocytes showed her to be a carrier of both deletions in addition to the normal CYBB sequence. This triple somatic mosaicism was confirmed with PCR-amplified genomic and complementary DNA. The presence of the normal CYBB gene in the mother was also proven by the finding of normal superoxide-generating neutrophils in addition to cells lacking this ability. Triple X syndrome was excluded. These findings suggest that the mutations are the result of an event in early embryogenesis of the mother, possibly involving a mechanism like sister chromatid exchange.

CYTOCHROME b IS PRESENT IN NEUTROPHILS FROM PATIENTS WITH CHRONIC GRANULOMATOUS DISEASE

The Lancet ◽  
1979 ◽  
Vol 313 (8123) ◽  
pp. 949-951 ◽  
Author(s):  
Niels Borregaard ◽  
KirstenStahr Johansen ◽  
Ebbe Taudorff ◽  
JohanH. Wandall
Keyword(s):  
Chronic Granulomatous Disease ◽  
Cytochrome B ◽  
Granulomatous Disease

scholarly journals Chronic Granulomatous Disease Presenting as Aseptic Ascites in a 2-Year-Old Child

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
J. F. Moreau ◽  
John A. Ozolek ◽  
P. Ling Lin ◽  
Todd D. Green ◽  
Elaine A. Cassidy ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Novel Mutation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Unknown Origin ◽  
Granulomatous Disease ◽  
Cybb Gene ◽  
Inherited Immunodeficiency ◽  
Peritoneal Biopsy ◽  
Immunodeficiency Syndrome

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected after identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children.

scholarly journals CD34+ peripheral blood progenitors as a target for genetic correction of the two flavocytochrome b558 defective forms of chronic granulomatous disease

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 53-58 ◽  
Author(s):  
F Li ◽  
GF Linton ◽  
S Sekhsaria ◽  
N Whiting-Theobald ◽  
JP Katkin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Chronic Granulomatous Disease ◽  
Peripheral Blood ◽  
B Lymphocyte ◽  
Leukemia Virus ◽  
Single Gene ◽  
Fold Increase ◽  
Granulomatous Disease ◽  
Flavocytochrome B558 ◽  
O2 Production

Abstract Chronic granulomatous disease (CGD) can result from any of four single gene defects involving components of the superoxide (O2-.)-generating phagocyte NADPH oxidase (phox). The phox transmembrane flavocytochrome b558 is composed of two peptides, gp91phox and p22phox. Mutations of gp91phox cause X-linked CGD, whereas mutations of p22phox cause one of the three autosomal recessive forms of CGD. We used the Maloney leukemia virus-based MFG retrovirus vector to produce replication defective retroviruses encoding gp91phox or p22phox. To maximize viral titer MFG retroviruses do not contain internal promoter or resistance elements. Epstein-Barr virus transformed B-lymphocyte cell lines (EBV- B) derived from normal individuals contain phox components and produce O2-., whereas those derived from CGD patients show the CGD defect. Transduction of gp91phox or p22phox-deficient CGD EBV-B lines resulted in correction of O2-. production from a barely detectable baseline to an average 7.2% and 13.8% of normal control, respectively, without any selective regimen to enrich for transduced cells. CD34+ hematopoietic progenitor cells, the therapeutic target for gene therapy of CGD, were isolated from peripheral blood of CGD patients, transduced with MFG- phox retroviruses, and differentiated in culture to mature phagocytes. Transduction of progenitors corrected the gp91phox (seven patients) and p22phox (two patients) CGD phagocyte oxidase defect to 2.5% and 4.9% of normal O2-. production, respectively, representing an 87-fold and 161- fold increase. These studies show correction of flavocytochrome b558- deficient CGD in primary hematopoietic progenitors, providing a basis for development of gene therapy for the X-linked gp91phox and autosomal p22phox-deficient forms of CGD.

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