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)

We have restudied two kindreds that formed the basis of the original report of autosomal recessive chronic granulomatous disease (CGD) associated with leukocyte glutathione peroxidase deficiency. Case 1 from the original study and the surviving brother of the originally reported case 2 both have severe CGD, with no detectable respiratory burst activity in purified intact neutrophils. However, their leukocytes exhibit normal glutathione peroxidase enzyme activity and gene expression. Examination of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase components known to be defective in CGD reveals no detectable cytochrome b558 nor any membrane activity in a cell-free NADPH oxidase assay system. Molecular analysis of the genes encoding cytochrome b558 subunits shows, in case 1, a C-->T substitution at nucleotide 688 of the gene encoding the gp91-phox subunit of cytochrome b558, resulting in a termination signal in place of Arginine-226. Levels of gp91-phox mRNA are markedly decreased despite normal levels of gene transcription, indicating a post-transcriptional effect of the nonsense mutation on mRNA processing or stability. The X-linked form of CGD developed in this cytogenetically normal female due to the uniform inactivation of the normal X chromosome in her granulocytes, indicated by the expression in her granulocyte mRNA of only one allele of a glucose-6-phosphate dehydrogenase polymorphisms for which she is heterozygous in genomic DNA. Case 2 (of the present study) has distinct mutations in each allele of the p22-phox gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic granulomatous disease and glutathione peroxidase deficiency, revisited. 794 43

We examined the molecular defect in two kindreds with "variant" X-linked chronic granulomatous disease (CGD). Western blots of neutrophil extracts showed decreased immunoreactive cytochrome b558 components gp91-phox and p22-phox. Analysis of mRNA demonstrated reduced gp91-phox transcripts, with relative preservation of an alternative mRNA species created by transcription initiation in the third exon of the gene. Single strand conformation polymorphism analysis of the 5' flanking region of the patients' gp91-phox genes revealed an electrophoretic abnormality not detected in 40 other gp91-phox genes. Genomic sequencing demonstrated a single base change associated with CGD in each kindred: in one, adenine to cytosine at base pair-57 and in the other, thymidine to cytosine at -55. These mutations are located between the "CCAAT" and "TATA" box consensus sequences involved in eukaryotic gene transcription. Gel shift assays revealed two specific DNA-protein complexes formed between phagocyte nuclear extracts and an oligonucleotide probe representing bases -31 to -68 of the gp91-phox promoter region; the faster-migrating complex could not be formed with oligonucleotides containing either of the promoter mutations. Thus, these promoter region mutations appear to be causally related to the loss of association of a DNA-binding protein and lead to diminished gp91-phox expression, abnormal transcription initiation, and the development of CGD.
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PMID:Mutations in the promoter region of the gene for gp91-phox in X-linked chronic granulomatous disease with decreased expression of cytochrome b558. 808 61

A patient was diagnosed as having chronic granulomatous disease (CGD). This case seems to have been transmitted in an X-linked from judging from the family history. We had previously suggested that the patient's cytochrome b was normal both qualitatively and quantitatively. Thus, we thought that there might be mutation in the gp91-phox (one of the two components of cytochrome b) gene affecting electron transport but leaving other functions intact. To confirm this speculation, we performed DNA analysis. Complementary DNA (cDNA) was obtained from messenger RNA (mRNA) derived from peripheral blood lymphocytes. By using primers specific for the gp91-phox cDNA, the cDNA was amplified by polymerase chain reaction (PCR). The amplified cDNA was then ligated into Blue Script vector and transfected into E. coli (JM109) in order to clone the cDNA of gp91-phox. Then, the cloned cDNA was sequenced. Sequence analysis showed that the nucleotides 1521-1525 were deleted and a new sequence of 8 nucleotides was substituted. This mutation converted Glu-Lys-Thr into His-Ile-Trp-Ala. To confirm that the mutated allele came from the patient's mother; we performed mismatched PCR. PCR using a mutated allele could produce approximately 250 base pair products only when the patient's cDNA was used. PCR using a wild type primer could produce 250 base pair products only when cDNA from a healthy donor was used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[DNA analysis of cytochrome b positive chronic granulomatous disease (a case report)]. 815 59

The superoxide-forming NADPH oxidase of human phagocytes is composed of membrane-bound and cytosolic proteins which, upon cell activation, assemble on the plasma membrane to form the active enzyme. Patients suffering from chronic granulomatous disease (CGD) are defective in one of the following components: p47-phox and p67-phox, residing in the cytosol of resting phagocytes, and gp91-phox and p22-phox, constituting the membrane-bound cytochrome b558. In an X-linked CGD patient we identified a novel missense mutation predicting an Asp-->Gly substitution at residue 500 of gp91-phox, associated with normal amounts of nonfunctional cytochrome b558 in the patient's neutrophils. In PMA-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, the association of the cytosolic proteins p47-phox and p67-phox with the membrane fraction of the patient was strongly disturbed. Furthermore, a synthetic peptide mimicking domain 491-504 of gp91-phox inhibited NADPH oxidase activity in the cell-free assay (IC50 about 10 microM), and the translocation of p47-phox and p67-phox in the cell-free translocation assay. We conclude that residue 500 of gp91-phox resides in a region critical for stable binding of p47-phox and p67-phox.
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PMID:A point mutation in gp91-phox of cytochrome b558 of the human NADPH oxidase leading to defective translocation of the cytosolic proteins p47-phox and p67-phox. 818 43

We have identified a cell surface ferric reductase activity in the fission yeast Schizosaccharomyces pombe. A mutant strain deficient in this activity was also deficient in ferric iron uptake, while ferrous iron uptake was not impaired. Therefore, reduction is a required step in cellular ferric iron acquisition. We have cloned frp1+, the wild-type allele of the mutant gene. frp1+ mRNA levels were repressed by iron addition to the growth medium. Fusion of 138 nucleotides of frp1+ promoter sequences to a reporter gene, the bacterial chloramphenicol acetyltransferase gene, conferred iron-dependent regulation upon the latter when introduced into S. pombe. The predicted amino acid sequence of the frp1+ gene exhibits hydrophobic regions compatible with transmembrane domains. It shows similarity to the Saccharomyces cerevisiae FRE1 gene product and the gp91-phox protein, a component of the human NADPH phagocyte oxidoreductase that is deficient in X-linked chronic granulomatous disease.
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PMID:The fission yeast ferric reductase gene frp1+ is required for ferric iron uptake and encodes a protein that is homologous to the gp91-phox subunit of the human NADPH phagocyte oxidoreductase. 832 Dec 36

Phagocytic cells are characterized by their ability to generate superoxide anions upon activation by appropriate stimuli. UM384, a myelomonocytic cell line, was shown to be defective in this oxidase activity as measured by nitroblue tetrazolium or cytochrome c reduction. Cytochrome b558, a unique pigment present in phagocytes and implicated in electron transfer from NADPH to O2, was absent in the differentiated UM384 cells. Both subunits of the cytochrome b558 appeared to be absent or present in strongly reduced amounts compared to the mother cell line U937, as indicated by immunocytochemistry or Western blot analysis using monoclonal antibodies (MABs). On the other hand, cytosolic factors also involved in NADPH oxidase activity were shown to be present, either immunologically or by using the capacity of the cytosol to activate the oxidase in a membrane fraction from bovine neutrophils. At the molecular level, the mRNA that encodes the gp91-phox was shown to be absent in the differentiated UM384 cells, whereas the mRNA that encodes the p22-phox was normally expressed. These results suggest that the defect in superoxide production by the UM384 cells is related to the absence of cytochrome b558, a situation mimicking that observed in phagocytes from patients with X-linked chronic granulomatous disease (X-CGD).
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PMID:Absence of both subunits of cytochrome b558 in the UM384 cell line relative to the inability to generate superoxide anions. 839 70

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of patients have defects in an X-linked gene (X-CGD) encoding gp91-phox, the large subunit of the membrane cytochrome b-245 component of NADPH oxidase. Epstein-Barr virus-transformed B-cell lines from patients with CGD provide a model system for the disease. We have used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from three unrelated patients with X-CGD. The protein is glycosylated and membrane associated, and the reconstituted oxidase is appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells is similar to that of normal B-cell lines. These data show the potential of gene therapy for this disease.
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PMID:X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox. 840 Feb 70

Chronic granulomatous disease is an uncommon inherited disorder of phagocytes in which the defective production of microbicidal oxidants leads to an enhanced susceptibility to bacterial and fungal infections. Despite the near uniform absence of the respiratory burst in CGD phagocytes, there is a striking clinical and genetic heterogeneity in this disorder. The recent elucidation of the molecular basis of CGD now provides an explanation for this heterogeneity. CGD is caused by a defect in any one of four components of NADPH oxidase, the enzyme responsible for the generation of the antimicrobial oxidants. X-linked inheritance is seen in approximately 65% of patients and results from mutations in the gene encoding the gp91-phox subunit of the cytochrome b558 component of the oxidase. The remaining 35% of patients inherit CGD in an autosomal recessive manner due to mutations in the genes encoding the remaining three oxidase components: p22-phox (chromosome 16), p47-phox (chromosome 7), and p67-phox (chromosome 1). Deletions, insertions, and point mutation leading to premature stop codons, amino acid substitutions, and splice site defects have all been identified. Most CGD patients have mutations unique to their families. The diversity of these mutations and the multiple genes affected provide an explanation for the clinical and genetic heterogeneity of CGD.
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PMID:Chronic granulomatous disease: the solving of a clinical riddle at the molecular level. 850 Feb 77

The immunochemical characterization of NADPH oxidase activity of cytochrome b558 purified from human neutrophils was determined after reconstitution in a cell-free assay using the native hemoprotein and recombinant purified cytosolic activating factors. The oxidase activity showed a strict dependence on the heme content at each step of the hemoprotein purification process. The immunochemical properties of the reconstituted oxidase made use of monoclonal antibodies raised against membrane-bound and octyl-glucoside-extracted cytochrome b. From nine specific monoclonal antibodies reacting with gp91-phox cytochrome b558, two were selected, both of which were found to bind to the beta subunit of cytochrome b558 and to inhibit superoxide formation in the oxidase reconstituted cell-free assay. The extent of inhibition was dependent on the phospholipid environment. Neutrophil membrane extracts from X-linked chronic granulomatous disease patients did not produce O2- in the reconstituted system and did not bind to the antibodies.
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PMID:Characterization of neutrophil NADPH oxidase activity reconstituted in a cell-free assay using specific monoclonal antibodies raised against cytochrome b558. 852 42

The primary immunodeficiencies are attractive candidates for the development of gene therapy approaches based on the transduction of hematopoietic cells. We have constructed a high-titer recombinant retrovirus for expression of gp91-phox, deficiencies of which cause the X-linked form of chronic granulomatous disease (X-CGD). We have used this vector to transduce human bone marrow, using either unfractionated mononuclear cells or purified CD34+ cells as targets and evaluated several infection protocols. Efficient gene transfer to progenitors and long-term culture-initiating cells (LTC-IC) was obtained for each target population. Importantly for potential clinical application, this could be achieved without the use of exogenous cytokines or polybrene. Progenitors representing each of the lineages detectable in vitro were transduced at equal efficiencies. The vector was shown partially to restore gp91-phox deficiency and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in transduced cells derived from X-CGD patients. These data demonstrate that it is possible to transduce primitive human hematopoietic cells efficiently and reconstitute NADPH oxidase.
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PMID:Efficient retroviral transduction of human bone marrow progenitor and long-term culture-initiating cells: partial reconstitution of cells from patients with X-linked chronic granulomatous disease by gp91-phox expression. 861 97


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