Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 a rare inherited immunodeficiency syndrome caused by a profound defect in the oxygen metabolic burst machinery. Activity of NADPH oxidase is absent or profoundly diminished, as at least one of its components (gp91(phox), p22(phox), p47(phox) and p67(phox)) is lacking or non-functional. This review explains the molecular basis of NADPH oxidase dysfunction by the effects of mutations in genes coding for particular oxidase components. Among the four types of CGD, the most common is X-linked CGD (approximately 65%), with defects in the CYBB gene encoding gp91(phox). A wide spectrum of mutations has been described in the CYBB gene with no predominant genotype. The second most common subtype of CGD caused by NCF1 mutation accounts for 30% of CGD patients and is inherited in an autosomal recessive manner, with predominance of a homozygotous deltaGT deletion in the genotype. The other two CGD subtypes having an autosomal recessive pattern together account for no more than 10% of CGD cases. A strategy for the molecular diagnostics in CGD patients is proposed and principles of genetic counseling are discussed here.
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PMID:Genetic and biochemical background of chronic granulomatous disease. 1517 25

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by mutations of one of the subunits of phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to decreased or complete absence of neutrophil oxidative burst. We report the clinical and laboratory findings in two young unrelated females 14 and 9 years of age and natives of Tahiti and Reunion Islands, respectively, with severe X-linked granulomatous disease. In both cases, the infectious pattern was unusual, with convergent symptoms suggesting underlying mycobacterial infection. Functional analysis revealed low residual NADPH oxidase activity with about 5-10% of normal neutrophil population. De novo null mutations affecting the CYBB gene that encodes the gp91 protein were found in both cases in the heterozygous state (in patient 1, p.Arg130X in exon 5, and in patient 2, a novel insertion in exon 6, c.632_633insCATC). Methylation analysis confirmed that phenotype expression was linked to skewed X inactivation and showed that the de novo mutation arose on the maternally inherited chromosome in one case and on the paternally inherited chromosome in the other case. In conclusion, X-linked CGD carriers could therefore be at risk for severe infectious diseases depending on the skewed X inactivation pattern and the infectious context.
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PMID:Severe X-linked chronic granulomatous disease in two unrelated females. 1708 90

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

X-linked chronic granulomatous disease (X-CGD) is an immunodeficiency disorder characterized by defective intracellular killing of microorganisms due to the neutrophils' inability to generate superoxide ions. Although it is always caused by mutations in the CYBB gene, clinical and molecular characteristics vary in different ethnic backgrounds. Two unrelated Thai boys presented with severe persistent pulmonary infections at the age of two months. Their abnormal dihydrorhodamine (DHR) flow cytometry assays supported the diagnosis of X-CGD. Mutation analysis was performed by polymerase chain reaction (PCR) amplification and sequencing of the entire coding regions of CYBB. Mutations identified were confirmed by restriction enzyme analyses. PCR-sequencing of the entire coding regions of CYBB identified nonsense mutations, 271C>T (R91X) in exon 4 and 456T>A (Y152X) in exon 5, in probands of each family. Both of the patients' mothers were found to be carriers. This observation supports that CYBB is the gene responsible for X-CGD across different populations and nonsense mutations are associated with severe phenotypes.
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PMID:Nonsense mutations of the CYBB gene in two Thai families with X-linked chronic granulomatous disease. 1840 98

This work investigated the functional role of nuclear factor-kappaB (NF-kappaB) in respiratory burst activity and in expression of the human phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes CYBB, CYBA, NCF1, and NCF2. U937 cells with a stably transfected repressor of NF-kappaB (IkappaBalpha-S32A/S36A) demonstrated significantly lower superoxide release and lower CYBB and NCF1 gene expression compared with control U937 cells. We further tested Epstein-Barr virus (EBV)-transformed B cells from patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), an inherited disorder of NF-kappaB function. Superoxide release and CYBB gene expression by EDA-ID cells were significantly decreased compared with healthy cells and similar to cells from patients with X-linked chronic granulomatous disease (X91(0) CGD). NCF1 gene expression in EDA-ID S32I cells was decreased compared with healthy control cells and similar to that in autosomal recessive (A47(0)) CGD cells. Gel shift assays demonstrated loss of recombinant human p50 binding to a NF-kappaB site 5' to the CYBB gene in U937 cells treated with NF-kappaB inhibitors, repressor-transfected U937 cells, and EDA-ID patients' cells. Zymosan phagocytosis was not affected by transfection of U937 cells with the NF-kappaB repressor. These studies show that NF-kappaB is necessary for CYBB and NCF1 gene expression and activation of the phagocyte NADPH oxidase in this model system.
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PMID:Essential role of nuclear factor-kappaB for NADPH oxidase activity in normal and anhidrotic ectodermal dysplasia leukocytes. 1947 Apr 38

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

Chronic-granulomatous disease (CGD) is a rare inherited primary immunodeficiency syndrome caused by a defective oxidative metabolism of phagocytic cells. Dysfunction of the membranous NADPH oxidase complex leads to a greatly increased susceptibility to severe fungal and bacterial infections, early in childhood. The most severe and frequent type of GCD is the X-linked transmitted form caused by mutations in the CYBB gene encoding the redox element of the oxidase complex, gp91phox or Nox2. However, very rare autosomal recessive CGD affecting other oxidase components than Nox2 are characterized by mild-clinical manifestations that could appear later at the adult age. Long-term antibiotic prophylaxis is essential to prevent infections associated with CGD, but approaches based on hematopoietic stem-cell transplantation and gene therapy offer valuable hope in a near future.
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PMID:[Chronic-granulomatous disease]. 1864 Jul 47

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by early onset of recurrent and severe infections. The molecular defects causing CGD are heterogeneous and lead to absence, low expression, or malfunctioning of one of the phagocyte NADPH oxidase components. It is known that mutations leading to CGD reside within the genes encoding four essential components of the oxidase designated as gp91-phox (phagocyte oxidase), p22-phox, p47-phox and p67-phox. gp91- together with p22-phox form the membrane cytochrome b(558) and play an essential role in the transfer of electrons following assembly of the active oxidase with the cytoplasmic p47- and p67-phox components. In hematopoietic cells, CYBB expression (the gene encoding gp91-phox) is limited to the granulocyte and monocyte/macrophage lineages during the process of terminal differentiation. CYBB is responsive to a number of inflammatory cytokines, especially interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). Cytokines have been also studied for activation of phagocytes respiratory burst. IFN-gamma stimulates superoxide release and is a prophylactic agent for CGD. It has been shown in vitro and in vivo to correct at least in part alterations of the oxidative metabolism, and to improve their microbicidal function. It has demonstrated clinical benefit in the majority of patients with CGD, reducing the relative risk of severe infections in 70%. In this study, we review mechanisms showing that IFN-gamma improves the splicing efficiency of CYBB gene transcripts in a particular group of CGD patients. The present article is an informative review of recent patents related to the use of interferon gamma therapy in chronic granulomatous disease.
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PMID:The use of interferon-gamma therapy in chronic granulomatous disease. 1899 4

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency affecting the innate immune system. Even if functional tests address the diagnosis of CGD, the identification of a molecular defect is essential for counselling family members at risk for being CGD carriers and for prenatal diagnosis. The X-linked form occurs in 65% of CGD patients. It is due to mutations in the CYBB gene, up to 12% of which are caused by large deletions. CGD carriers are usually healthy, and molecular analysis is essential to reveal their carrier status. The aim of this study was to apply a gene dosage approach, using SYBR green quantitative real-time polymerase chain reaction (RT-PCR), to quantify the genomic copy number in carriers and noncarriers of gross deletions covering the region of the CYBB gene. We studied the expression of two different amplification products of the CYBB gene, and the results confirmed a highly reduced expression of the gene in the carrier samples. The results were confirmed by linkage analysis and fluorescence in situ hybridization. Quantitative real-time PCR is fast and simple to perform, and we propose it as a new routine diagnostic approach to detect CGD carriers of deletions covering the region spanning the CYBB gene.
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PMID:Identification of deletion carriers in X-linked chronic granulomatous disease by real-time PCR. 1983 55


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