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 characterized by defects in the superoxide producing enzyme NADPH oxidase causing phagocytes to improperly clear invading pathogens. Here we report findings of a late presenting 16-year-old female with X-linked CGD. The patient presented with community-acquired pneumonia, but symptoms persisted for 2 weeks during triple antimicrobial coverage. Cultures revealed Aspergillus fumigatus which was resolved through aggressive voriconazole treatment. Neutrophil studies revealed NADPH oxidase activity and flavocytochrome b(558) levels that were 4-8% of controls and suggested carrier status of the mother. We found a null mutation in the CYBB gene (c.252insAG) predicting an aberrant gp91(phox) protein (p.Cys85fsX23) in the heterozygous state. Methylation analysis demonstrated extremely skewed X chromosome inactivation favoring the maternally inherited defective gene. In conclusion, a novel mutation in the CYBB gene and an extremely skewed X-inactivation event resulted in the rare expression of the CGD phenotype in a carrier female.
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PMID:X-linked chronic granulomatous disease secondary to skewed X chromosome inactivation in a female with a novel CYBB mutation and late presentation. 1900 69

A patient with previously unrecognized X-linked chronic granulomatous disease (X-CGD) died of multi-organ failure, secondary to ongoing infection and hemophagocytic lymphohistiocytosis (HLH). Post mortem histological investigations were compatible with X-CGD, and a CYBB gene mutation was confirmed. No homozygous mutations in the genes encoding perforin (PRF1), MUNC 13-4 or syntaxin-11 (STX11) were found; however, there was a heterozygous alteration c.1471G>A in the PRF1 gene causing a p.Asp491Asn substitution. Although this substitution has not been reported to cause primary or secondary HLH, we speculate that it may have made the patient more susceptible for HLH under the circumstances of ongoing infection associated with X-CGD.
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PMID:Fatal hemophagocytic lymphohistiocytosis in X-linked chronic granulomatous disease associated with a perforin gene variant. 1905 15

Patients with chronic granulomatous disease (CGD) suffer from severe bacterial and fungal infections and deregulated inflammation, which are often associated with granuloma formation. We describe a 2-year-old boy who was seemingly healthy at the age of 1 year when a conventional chest radiograph was taken to exclude pulmonary aspiration of a piece of apple. Incidentally, a space-occupying mediastinal mass was revealed that was further evaluated by magnetic resonance imaging. Varying solid and also cystic, septated parts of the mass could be discerned and it was considered to be a teratoma. Removal of the mass by surgery was arduous because of adhesiveness to surrounding areas and led to severe complications. Unexpectedly, histopathologic examination revealed massive acute granulomatous inflammation with liquefied thymic cysts. X-linked CGD was subsequently diagnosed by a dihydrorhodamine 123 assay and sequencing of the CYBB gene (hotspot mutation c.742-743insA). This is the third example that we are aware of, where CGD granulomas were mistaken for neoplasms. The other 2 patients were initially believed to have tumors of the stomach and the urinary bladder, respectively. All patients initially received inadequate treatment. We discuss possible strategies to avoid such tragic confusions.
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PMID:Chronic granulomatous disease (CGD) mimicking neoplasms: a suspected mediastinal teratoma unmasking as thymic granulomas due to X-linked CGD, and 2 related cases. 1913 70

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 a rare inherited disorder in which phagocytes fail to produce antimicrobial superoxide because NADPH oxidase activity is absent. In about 65% of the cases, the disease is due to mutations affecting the X-linked CYBB gene, encoding the gp91(phox) subunit of NADPH oxidase. We investigated 34 CGD male patients by DHPLC and direct sequencing. A mutation was found in the CYBB gene of 33 patients and 9 of these were novel: one non-sense mutation (c.1123 G>T), three missense mutations (c.58G>A; c.1076 G>C; c.1357 T>A), two splice site mutations (c.141+5G>T; c.142-1G>A), one duplication (c.42_45dupCATT), one deletion (c.184delT), and one rare deletion of two non-contiguous nucleotides (c.1287delT+c.1290delC). One patient had the most frequent GT homozygous deletion in exon2 of the NCF-1 gene encoding the p47(phox) subunit of NADPH oxidase. The carrier analysis was performed in 23 patients' mothers and 16 female relatives through molecular and FISH studies. No clear correlation between the severity of clinical symptoms and the type of mutation could be demonstrated. This study further supports the great heterogeneity of the disease and the notion that genetic analysis is a critical step in obtaining a definitive diagnosis for CGD.
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PMID:Molecular characterization of a large cohort of patients with Chronic Granulomatous Disease and identification of novel CYBB mutations: an Italian multicenter study. 1941 Feb 94

This article reports an atypical and extremely rare case of X-linked CGD in an Italian family characterized by a low expression of gp91phox (X91- CGD). A novel point mutation in the CYBB gene's promoter (insertion of a T at position -54T to -56T) appeared to prevent the full expression of this gene in the patient's neutrophils and correlated with a residual oxidase activity in the whole cells population. The expression and functional activity of the oxidase in eosinophils appeared to be almost normal. Gel shift assays indicated that the mutation led to decreased interactions with DNA-binding proteins. The total O2- production in the patient's granulocytes (5-7% of normal) supported no microbicidal power after 45 min and 60 min of contact with S. aureus and C. albicans, respectively. Despite this residual oxidase activity, the patients suffered from severe and life-threatening infections. It was concluded that in these X91- CGD neutrophils, the O2- production per se was not sufficient to protect the patient against severe infections.
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PMID:A novel point mutation in the CYBB gene promoter leading to a rare X minus chronic granulomatous disease variant--impact on the microbicidal activity of neutrophils. 1970 27

OTC deficiency, a partially dominant X-linked trait, is the most frequent inborn error of the urea cycle. We describe a female patient with a contiguous gene deletion syndrome encompassing the OTC, DMD, RPGR, CYBB and XK genes, amongst others, only manifesting features of OTC deficiency. Molecular characterization was ascertained by MLPA and confirmed by CGH microarray, which revealed an 8.7 Mb deletion of the X-chromosome. Complete de novo deletion of the OTC gene led to a severe clinical phenotype in the proband. The application of high resolution molecular genetic techniques such as MLPA and array CGH, in mutation negative OTC cases allows the identification of chromosomal rearrangements, such as large deletions and provides information for accurate genetic counseling and prenatal diagnosis.
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PMID:Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency. 1978 89

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

High resolution melting is a new method of genotyping and variant scanning that can be seamlessly appended to PCR amplification. Limitations of genotyping by amplicon melting can be addressed by unlabeled probe or snapback primer analysis, all performed without labeled probes. High resolution melting can also be used to scan for rare sequence variants in large genes with multiple exons and is the focus of this article. With the simple addition of a heteroduplex-detecting dye before PCR, high resolution melting is performed without any additions, processing or separation steps. Heterozygous variants are identified by atypical melting curves of a different shape compared to wild-type homozygotes. Homozygous or hemizygous variants are detected by prior mixing with wild-type DNA. Design, optimization, and performance considerations for high resolution scanning assays are presented for rapid turnaround of gene scanning. Design concerns include primer selection and predicting melting profiles in silico. Optimization includes temperature gradient selection of the annealing temperature, random population screening for common variants, and batch preparation of primer plates with robotically deposited and dried primer pairs. Performance includes rapid DNA preparation, PCR, and scanning by high resolution melting that require, in total, only 3h when no variants are present. When variants are detected, they can be identified in an additional 3h by rapid cycle sequencing and capillary electrophoresis. For each step in the protocol, a general overview of principles is provided, followed by an in depth analysis of one example, scanning of CYBB, the gene that is mutated in X-linked chronic granulomatous disease.
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PMID:High resolution melting analysis for gene scanning. 2008 14

High-resolution melting analysis was applied to X-linked chronic granulomatous disease, a rare disorder resulting from mutations in CYBB. Melting curves of the 13 PCR products bracketing CYBB exons were predicted by Poland's algorithm and compared with observed curves from 96 normal individuals. Primer plates were prepared robotically in batches and dried, greatly simplifying the 3- to 6-hour workflow that included DNA isolation, PCR, melting, and cycle sequencing of any positive products. Small point mutations or insertions/deletions were detected by mixing the hemizygous male DNA with normal male DNA to produce artificial heterozygotes, whereas detection of gross deletions was performed on unmixed samples. Eighteen validation samples and 22 clinical kindreds were analyzed for CYBB mutations. All blinded validation samples were correctly identified. The clinical probands were identified after screening for neutrophil oxidase activity. Nineteen different mutations were found, including seven near intron-exon boundaries predicting splicing defects, five substitutions within exons, three small deletions predicting premature termination, and four gross deletions of multiple exons. Ten novel mutations were found, including (c.) two missense (730T>A, 134T>G), one nonsense (90C>A), four splice site defects (45 + 1G>T, 674 + 4A>G, 1461 + 2delT, and 1462-2A>C), two small deletions (636delT, 1661_1662delCT), and one gross deletion of exons 6 to 8. High-resolution melting can provide timely diagnosis at low cost for effective clinical management of rare, genetic primary immunodeficiency disorders.
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PMID:Rapid genetic analysis of x-linked chronic granulomatous disease by high-resolution melting. 2030 42


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