Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic granulomatous disease (CGD) is a primary immunodeficiency that affects the oxidative mechanism of microbial killing of phagocytic cells. The defect is characterized by a lack or severely reduced superoxide anion (O2-) production by phagocytes. Seventy percent of CGD cases are X-linked (X-CGD) and they are caused by mutations in the gene encoding for gp91(phox), one of the two subunits of the flavocytochrome b558 of the NADPH oxidase. We identified an abnormal transcript arising from a novel splice site mutation within the gene encoding gp91(phox), which suggested that the mutation affected normal mRNA splicing. Thus, the effect of this mutation leads to the complete absence of the flavocytochrome b558 in neutrophil membranes, which caused the biochemical phenotype X91 degrees-CGD in this family. These molecular findings help to explain the early onset and severe phenotype in this X-CGD kindred.
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PMID:Molecular characterization of a novel splice site mutation within the CYBB gene leading to X-linked chronic granulomatous disease. 1546 10

Chronic granulomatous disease (CGD) is a rare inherited disorder in which antimicrobial activity of phagocytes is impaired due to the lack of reactive oxygen species, or oxidative burst, produced by NADPH oxidase. The X-linked form of CGD, representing approximately 70% of all cases, is caused by mutations in the cytochrome b beta subunit (CYBB) gene, which maps to chromosome Xp21.1. CYBB encodes the gp91-phox protein, a necessary component in the NADPH oxidase pathway. A wide variety of mutations have been identified in X-linked CGD patients, all of which lead to deletion of the functional protein and no oxidative burst activity. The mutations vary from single nucleotide substitutions to deletions of the entire gene. In this article, we report a mutation detection method for probands of female relatives at risk for carrier status of large deletions of the CYBB gene. Through fluorescent in situ hybridization of metaphase chromosomes, we were able to consistently distinguish carriers from noncarriers using polymerase chain reaction-derived, labeled DNA specific for exons 2 to 13 of the CYBB region at Xp21.1.
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PMID:Long polymerase chain reaction-based fluorescence in situ hybridization analysis of female carriers of X-linked chronic granulomatous disease deletions. 1585 41

A case of splenic abscesses caused by Paecilomyces variotii in a 21-month-old child with previously undiagnosed chronic granulomatous disease (CGD) is described. An X-linked form of CGD with deficiency of gp91-phox was diagnosed. The fungal pathogen was isolated from the abscess contents. Cure was achieved by a partial splenectomy and a prolonged fluconazole and flucytosine combination treatment regimen. P. variotii is an emerging fungus in children with CGD. Every effort should be made to recover the possible underlying immunodeficiency in children with paecilomycosis.
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PMID:Successful treatment of Paecilomyces variotii splenic abscesses: a rare complication in a previously unrecognized chronic granulomatous disease child. 1616 19

The objective of this study was to determine the utility of anti-nuclear antibody (ANA) testing in the investigation of cutaneous and other lupus symptoms in female carriers of X-linked chronic granulomatous disease (CGD). We undertook a prospective study of 19 carrier mothers attending our institution, with direct questioning of carriers concerning symptoms and testing for anti-nuclear and anti-phospholipid antibodies. A total of 58% reported significant photosensitive skin rashes, 42% reported mouth ulcers and 37% complained of joint pains that could not be attributed to other known causes. Anti-nuclear antibody (ANA) testing was negative in 73% of all carriers. The five positive ANAs were of low titre (maximum 1 : 320 on Hep 2 cells in two women) and only one weak positive double-stranded DNA antibody and no extractable nuclear antibodies were found. Several of the mothers, despite negative serology, benefited from referral to a specialist, and in some cases to specific treatment. A history of skin rashes, joint pain, fatigue and mouth ulcers should be sought actively in the female relatives of X-CGD patients but negative lupus serology should not preclude referral to appropriate dermatology or rheumatology services. as symptoms may respond well to appropriate treatment.
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PMID:Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology. 1728 62

Chronic granulomatous disease (CGD) is a hereditary illness generally occurring in childhood, in the form of recurrent severe infections. The main pathogens are staphylococci and aspergilli. It results from a failure of professional phagocytes, and particularly neutrophils, to produce superoxide ions O2- and their derivatives, which protect cells from bacterial, invasion through an oxidative and toxic defence mechanism. At an infection site. contact between the neutrophils and microorganisms or an inflammatory mediator triggers a respiratory burst, which results in the activation of the NADPH oxidase enzyme complex. NADPH depletes surrounding oxygen to yield O2-. In its active form. NADPH oxidase is an assembly of two components, namely the membrane cytochrome b558 (consisting o two subunits, gp91-phox and p22-phox) and soluble protein factors present in the resting neutrophil cytoplasm. Transfer of these cytosolic factors and their anchorage to cytochrome b558 determines the activity of NADPH oxidase. The respiratory burst lasts no more than a few minutes, but the precise mechanisms underlying its termination are not well known. In chronic granulomatous disease, neutrophils have lost their bactericidal capacity The most frequent form is hereditary and X-linked; in this case, the affected gene is CYBB, which encodes gp91-phox, the catalytic subunit of cytochrome b558. In autosomal and recessive forms of CGD the mutations affect the genes encoding p22-phox, p67-phox or p47-phox. We have unraveled the assembly mechanisms of the NADPH oxidase complex and have demonstrated that the cytosolic factor p67-phox is the determining element: it triggers both the assembly and the activation of NI4DPH oxidase. Binding of p67-phox to cytochrome b558 induces a gradual conformational change of cytochrome b558, which then becomes capable of transferring electrons produced in the cytoplasm from NADPH to oxygen, reducing the latter to O2-. The isolation of NADPH oxidase in its active and assembled form has allowed us to identify the activation partners of the oxidase complex. We also demonstrated that calcium-binding myeloid-related proteins (MRP). that are abundant in neutrophil cytoplasm, play a fundamental role in this activation. CGD patient management is essentially based on long-term high-dose prophylactic antibiotic administration. Gene therapy is promising but some distance away from practical application. We are currently investigating a new therapeutic concept that consists of transferring cytochrome b558 protein directly into deficient cells (initially the PLB 985 X cell line), encapsulated in proteoliposomes, which are hydrophobic.
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PMID:[Molecular aspects of chronic granulomatous disease. "the NADPH oxidase complex"]. 1796 55

Mutations in any of four known NADPH-oxidase components lead to CGD. X-linked CGD (X-CGD) is caused by defects in CYBB, the gene that encodes gp91-phox. Autosomal recessive (AR) CGD is caused by defects in the genes for p47 phox, p22-phox or p67-phox. The aim of this study was to screen the molecular defect in the fetus of an X-CGD carrier mother and postnatal confirmation of the results. In a family whose first-born child died from X-CGD, fetal DNA was obtained from an ongoing pregnancy by chorionic villus sampling (CVS). Direct sequencing was used to detect the previously identified CYBB gene mutation. The NADPH oxidase activity in the neutrophils from the carrier mother and from the newborn was analyzed by the DHR assay. Our studies predicted that the fetus in question was not affected by chronic granulomatous disease, which was demonstrated to be correct at birth. For prenatal screening in a pregnant X-CGD carrier, direct sequencing is a good method for detecting the mutation in the fetal DNA. Postnatal confirmation of results with the DHR assay is more practical than mutation screening to show whether the newborn have normal NADPH oxidase activity or does not.
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PMID:Prenatal diagnosis of chronic granulomatous disease in a male fetus. 1927 61

Chronic granulomatous disease (CGD) is associated with significant morbidity and mortality from infection. The first CGD gene therapy trial resulted in only short-term marking of 0.01% to 0.1% of neutrophils. A recent study, using busulfan conditioning and an SFFV retrovirus vector, achieved more than 20% marking in 2 patients with X-linked CGD. However, oxidase correction per marked neutrophil was less than normal and not sustained. Despite this, patients clearly benefited in that severe infections resolved. As such, we initiated a gene therapy trial for X-CGD to treat severe infections unresponsive to conventional therapy. We treated 3 adult patients using busulfan conditioning and an MFGS retroviral vector encoding gp91(phox), achieving early marking of 26%, 5%, and 4% of neutrophils, respectively, with sustained long-term marking of 1.1% and 0.03% of neutrophils in 2 of the patients. Gene-marked neutrophils have sustained full correction of oxidase activity for 34 and 11 months, respectively, with full or partial resolution of infection in those 2 patients. Gene marking is polyclonal with no clonal dominance. We conclude that busulfan conditioning together with an MFGS vector is capable of achieving long-term correction of neutrophil oxidase function sufficient to provide benefit in management of severe infection. This study was registered at www.clinicaltrials.gov as #NCT00394316.
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PMID:Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils. 1996 57

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations.
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PMID:Hematologically important mutations: X-linked chronic granulomatous disease (third update). 2072 9

X-linked chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by a defect in the gp91(phox) gene. In an effort to treat X-CGD, we investigated the safety and efficacy of gene therapy using a retroviral vector, MT-gp91. Two X-CGD patients received autologous CD34(+) cells transduced with MT-gp91 after a conditioning regimen consisting of fludarabine and busulfan. The level of gene-marked cells was highest at day 21 (8.3 and 11.7% in peripheral blood cells) but decreased to 0.08 and 0.5%, respectively, 3 years after gene transfer. The level of functionally corrected cells, as determined by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, reached a peak at day 17 (6.5% patient 1 (P1) and 14.3% patient 2 (P2) of total granulocytes) and declined to 0.05% (P1) and 0.21% (P2), 3 years later. Some retroviral vectors were found to have integrated within or close to the proto-oncogenes MDS1-EVI1, PRDM16, and CCND2; however, no abnormal cell expansion or related hematological malignancy was observed. Overall, the gene transfer procedure did not produce any serious adverse effects and was able to convert a significant fraction of blood cells to biologically functional cells, albeit for a short period of time.
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PMID:Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial. 2187 3

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency disorder characterized by recurrent purulent infections of the skin, lungs, and reticuloendothelial organs, primarily due to staphylococci, enteric bacteria, fungi, and occasionally mycobacteria. More than two thirds of all cases are X-linked and result from defects in the CYBB gene that encodes the gp91-phox subunit of NADPH oxidase. The authors present a case of a three month old child admitted with a metacarpic steomyelitis by Serratia marcescens. Studies confirmed an abnormal respiratory burst in activated neutrophils and absence of gp91-phox expression on patient and a brother (with previous Nocardia infection). Both hemizygous for a pathogenic mutation detected in exon 3 of CYBB gene (c.252 G>A, p.Ala84Ala), a variant that affects the splicing. At two years of age he is still on prophylaxis with cotrimoxazol and itraconazol, without relevant complications. CGD is rare but must be evocated in cases of uncommon or atypical infections.
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PMID:[Serratia osteomyelitis and chronic granulomatous disease]. 2201 33


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