Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

A 10-month-old Japanese male infant, with no history of being prone to infections, contracted an intrapulmonary mycobacterial infection. After 2 months of intermittent fever, radiological examinations revealed mass lesions in the lung and mediastinum. Biopsy specimens showed granulomas with caseous necrosis, from which Mycobacterium avium was isolated. There was no history of mycobacteriosis or immunodeficiency diseases among his relatives. Analyses of the O2- release and expression of NADPH oxidase components verified that he suffered from gp91-phox- chronic granulomatous disease (CGD), and that his mother was a carrier of the disease. This is a rare clinical presentation for the onset of CGD, suggesting that the invasive mycobacteriosis might result from defective intracellular killing of CGD-phagocytes.
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PMID:Intrapulmonary Mycobacterium avium infection as the first manifestation of chronic granulomatous disease. 913 39

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thirds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form of CGD bicistronic retroviral vectors containing the gp91-phox gene and a selectable marker gene were constructed. The ability of these vectors to restore NADPH oxidase activity was tested in a human myeloid leukemic cell line that is defective in superoxide production, as well as in primary CD34+ cells obtained from X-CGD patients. Under optimal conditions 80% of the CD34+ cells derived from bone marrow of one X-CGD patient were transduced. The level of superoxide production, in phagocytes derived from transduced cells was 68.9% of normal levels. Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present experiments provide the basis for the development of a gene replacement therapy for the X-linked form of CGD.
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PMID:Gene therapy of chronic granulomatous disease. 1093

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by defects in leukocyte NADPH oxidase. Various inherited defects in one of the membrane-bound components of NADPH oxidase, gp91-phox, cause X-linked (X91) CGD. Analysis of three patients with X91 CGD revealed that different mechanisms of molecular quality control lead to the common phenotype of absence of mature membrane-bound NADPH oxidase complex in leukocytes. In the first patient, aberrant intron splicing created a premature stop codon. However, the mutant mRNA was degraded prematurely, which prevented the production of truncated protein. In the second patient, a frameshift mutation with the potential to generate a gp91-phox polypeptide, with an aberrant and elongated C-terminus, led to barely detectable levels of gp91-phox, even though the reported functional domains of the protein appeared unaffected. In the third patient, a point mutation created a single amino acid change in the predicted FAD-binding site of gp91-phox. Although gp91-phox was detectable with Western blotting, no cytochrome b(558) was expressed on the cell surface. These analyses showed that molecular quality control machinery plays an important role in the pathogenesis of CGD, not only in the X910 but also in the X91- form of this X-linked disease.
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PMID:Molecular quality control machinery contributes to the leukocyte NADPH oxidase deficiency in chronic granulomatous disease. 1199 79

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from defects in the multienzyme complex NADPH-oxidase (phagozyte oxidase, phox), which normally produces microbicidal reactive oxygen metabolites (ROM). The reason for our patient's CGD was unusual, as revealed by the following in vitro findings in neutrophils and EBV-transformed B-cells: lack of flavocytochrome b(558) expression, restoration of significant ROM production after transduction with gp91-phox cDNA by a retrovirus vector, an 879G-->A, Trp289-->Stop mutation in one X chromosomal gp91-phox allele, a one-sided paternal X chromosome inactivation, as shown by a lyonization assay at the HUMARA locus, and the result of a dihydrorhodamine 123 flow cytometry assay revealing consistently that 1 in 2500 neutrophils produced ROM at normal levels. Our conclusion: A presumed autosomal form of CGD has been excluded. Instead, a spontaneous mutation in gp91-phox coinciding with an extreme X chromosome inactivation ratio resulted in X-linked CGD in this young woman.
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PMID:Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation. 1469 45

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

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

CYBB encodes the gp91-phox protein of the phagocytic NADPH oxidase; the innate immunity-related enzymatic complex responsible for the respiratory burst. Mutations in CYBB can cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by ineffective microbicidal activity, for which over 150 family-specific mutations have been described. It is also plausible that common SNPs in CYBB alter the expression or function of gp91-phox, determining differences in susceptibility to complex disorders such as autoimmune or infectious diseases. We have resequenced the exons, UTRs, and intronic regions of CYBB in 102 ethnically diverse individuals and genotyped nine tag-SNPs in 942 individuals from 52 worldwide populations. The 28 observed SNPs (none of which nonsynonymous) reside on 28 haplotypes that can be collapsed into five clades. CYBB shows lower diversity than other X-chromosome genes and most of the between-population genetic variance was observed among Africans and non-Africans. The African population shows the highest diversity and the lowest linkage disequilibrium (LD). Because there is extensive shared LD among non-Africans, tag-SNPs can be effectively employed in gene-centric association studies and are portable across Eurasian and Native American populations. Comparison of CYBB coding sequences among mammals evidences the action of long-term purifying selection, which is stronger on the C-terminal cytosolic domain than on the N-terminal transmembrane domain of gp91-phox.
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PMID:CYBB, an NADPH-oxidase gene: restricted diversity in humans and evidence for differential long-term purifying selection on transmembrane and cytosolic domains. 1827 5

Chronic granulomatous disease (CGD) is an inherited disorder of pathogen killing by phagocytic leukocytes caused by mutations in NADPH oxidase subunits. Patients with CGD have life-threatening bacterial and fungal infections. Children's Medical Center at Tehran University is the referral center for immunodeficiency in Iran. During 2 years of study, 11 non-consanguineous families with clinically diagnosed CGD were referred to this center. In functional assays performed on neutrophils from affected children and their mothers; no activity or strongly decreased oxidase activity was detected in the patients' cells. In oxidase tests that scored this activity on a per-cell basis, a mosaic pattern was detected in the neutrophils from all 11 mothers. Western blot analysis revealed an X91 degrees phenotype in all patients. Mutation screening in the CYBB gene encoding gp91(phox) by SSCP analysis followed by sequencing showed nine different mutations, including two novel mutations. The present survey is the first study aimed to analyze the clinical features and the molecular diagnosis of X-CGD in Iranian patients.
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PMID:Molecular diagnosis of X-linked chronic granulomatous disease in Iran. 1832 77

Chronic granulomatous disease (CGD) is a primary immunodeficiency of defective neutrophil oxidative burst activity due to mutations in the genes CYBA, NCF-1, NCF-2, and CYBB, which respectively encode the p22-phox, p47-phox, p67-phox, and gp91-phox subunits. CGD usually presents in early childhood with recurrent or severe infection with catalase-positive bacteria and fungi. We present an unusual case of CGD in which Burkholderia cepacia lymphadenitis developed in a previously healthy 10-year-old girl. Flow cytometric analysis of dihydrorhodamine (DHR)-labeled neutrophils performed by a CLIA-approved outside reference laboratory was reported as normal. However, we found that this patient's neutrophil oxidative burst activity in DHR assays was substantially reduced but not absent. A selective decrease in intracellular staining for p67-phox suggested the diagnosis of autosomal recessive CGD due to NCF-2 gene mutations, and a novel homozygous and hypomorphic NCF-2 gene mutation was found. The potential mechanisms for this delayed and mild presentation of CGD are discussed.
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PMID:Focus on FOCIS: the continuing diagnostic challenge of autosomal recessive chronic granulomatous disease. 1862 37


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