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 recently reported that the RD114-pseudotyped MFGS-gp91phox vector achieves unprecedented levels of correction of the NADPH-oxidase gp91phox (approved gene symbol CYBB) defect in CD34(+) cells from patients with X-linked chronic granulomatous disease in the NOD/SCID mouse model. Considering clinical use of this vector, we transplanted autologous mobilized peripheral blood CD34(+) progenitor cells, transduced with the RD114-MFGS-gp91phox vector, into two healthy rhesus macaques following nonmyeloablative conditioning. The moderately high levels of in vivo marking seen in the first months following transduction decreased and stabilized at about 8 months posttransplant. Marking for both healthy animals after 15 months was 0.3 to 1.3 vector copies per 100 cells in lymphocytes, neutrophils, and monocytes. Vector insertion analyses performed by linear amplification-mediated PCR and sequencing identified 32 and 45 separate insertion sites in the animals. Identical insertion sites were found in myeloid cells and lymphocytes, demonstrating the successful transduction of lymphomyeloid progenitors. Some inserts landed in the vicinity of genes controlling cell cycle and proliferation. Statistical analyses of insertion sites 1 year posttransplant suggest a high diversity of insertion sites despite low marking.
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PMID:Polyclonal long-term MFGS-gp91phox marking in rhesus macaques after nonmyeloablative transplantation with transduced autologous peripheral blood progenitor cells. 1660 Jun 88

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

The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.
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PMID:Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. 1730 Aug 82

A few known primary immunodeficiencies confer predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines (regional disease, known as BCG-itis, or disseminated disease, known as BCG-osis), or more virulent mycobacteria, such as Mycobacterium tuberculosis (pulmonary and disseminated tuberculosis). We investigated the clinical and genetic features of a 12-year-old boy with both recurrent BCG-osis and disseminated tuberculosis. The patient's phagocytic cells produced no O(2)(-). A hemizygous splice mutation was found in intron 5 of CYBB, leading to a diagnosis of X-linked chronic granulomatous disease. Chronic granulomatous disease should be suspected in all children with BCG-osis, even in the absence of nonmycobacterial infectious diseases, and in selected children with recurrent BCG-itis or severe tuberculosis.
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PMID:BCG-osis and tuberculosis in a child with chronic granulomatous disease. 1754 93

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

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

We evaluated a boy who had multiple Salmonella septicemia, Aspergillus pneumonia and brain abscesses. His nitroblue tetrazolium (NBT) test was reportedly abnormal. The dihydrorhodamine (DHR) flow cytometry assay was compatible with typical X-linked chronic granulomatous disease (X-CGD). CYBB analysis revealed a novel complex mutation atggacg --> ttca in exon 12 (base pairs 1532-1538). As a result, 3 amino acids Tyr 511, Gly 512 and Arg 513 were deleted and replaced by 2 amino acids, Phe and Gln. The DHR and mutation analysis of his mother showed normal DHR pattern and no mutations in exon 12 of CYBB gene. In conclusion, any children with multiple Salmonella and Aspergillus infection should be suspected of CGD. NBT test, DHR assay and gene analysis are helpful toolsto confirm the diagnosis e v en i n the case of de novo mutation.
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PMID:A novel mutation of the CYBB gene resulting in severe form of X-linked chronic granulomatous disease. 1905 37

We report a 28-year-old woman patient suffering from refractory subcutaneous abscess. Stimuli-induced microbicidal reactive oxygen metabolites formation test of the patient's neutrophils revealed that only 9.6% of the neutrophils produced H2O2. DNA analysis of the CYBB that encodes gp91(phox) demonstrated that she was heterozygous for a nonsense mutation, 206Trp(TGG)/stop(TGA) and therefore, a diagnosis of adult onset X-linked chronic granulomatous disease was made. Our molecular biological study revealed that her disease was caused by a de novo mutation in the CYBB gene on the paternal-origin X-chromosome and a skewed inactivation of the normal maternal X-chromosome.
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PMID:Adult onset X-linked chronic granulomatous disease in a woman patient caused by a de novo mutation in paternal-origin CYBB gene and skewed inactivation of normal maternal X chromosome. 1852 Jan 20

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 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


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