Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis

Sanquin Research, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Plesmanlaan 125, 1066 CX, Amsterdam, The Netherlands.
Blood Cells Molecules and Diseases (Impact Factor: 2.65). 10/2010; 45(3):246-65. DOI: 10.1016/j.bcmd.2010.07.012
Source: PubMed


Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations.

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    • "The most common mutations found in the CYBB gene were single nucleotide substitutions, followed by insertions, deletions and combinations of small deletions and insertions.19 In a recent study, however, nonsense or missense mutations represented 35% of mutations, while splice site mutations, and deletions or insertions comprised 18% and 43% of mutations, respectively.20 An international X-CGD database including over 300 CYBB mutations19,21 showed that most mutations were found throughout the 13 exons or at exon/intron boundaries, and that almost 200 of these mutations were unique.22 "
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    ABSTRACT: Chronic granulomatous disease (CGD) is a rare immunodeficiency disease, which is characterized by the lack of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. The disease presents leukocytosis, anemia, hypergammaglobulinemia, and granuloma formation of the skin, lung, or lymph nodes. The mutation of the CYBB gene encoding gp91phox, located on chromosome Xp21.1 is one of the causes of CGD. We report a patient with X-linked CGD who carried a novel mutation, a c.1133A>G (paAsp378Gly) missense mutation, in the CYBB gene.
    Full-text · Article · Jul 2014 · Allergy, asthma & immunology research
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    • "Based on clinical history, laboratory data, granulomas on histology, and cutaneous infection from Serratia, CGD was diagnosed. CYBB gene sequencing for gp91phox, a membrane-bound subunit of NADPH oxidase, ultimately confirmed the diagnosis of X-linked CGD [1,2,5]. "
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    ABSTRACT: Background Chronic granulomatous disease is a rare inherited disorder of the innate immune system. In patients with a clinical history of recurrent or persistent infections, especially infections caused by uncommon species, chronic granulomatous disease should be considered. Case presentation We report the case of a 5-year-old boy with a presumptive diagnosis of Crohn’s disease with extraintestinal manifestations. Chronic granulomatous disease was suspected in this case after Serratia marcescens was isolated from a skin ulcer culture. Granulomas were confirmed on histology and chronic granulomatous disease was diagnosed. Conclusion This case emphasizes the importance of high clinical suspicion of an alternative diagnosis of immune deficiency in patients with presumed inflammatory bowel disease and opportunistic infections, especially when disease occurs in early life.
    Full-text · Article · Jun 2014 · BMC Pediatrics
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    • "Moreover, we found no indication for expression of the mutation in the mother's neutrophils. Although CYBB wt/mut females do not usually suffer from CGD, their phagocyte populations often display heterogeneous patterns of gp91 phox expression and superoxide production due to random X-chromosome inactivation [Roos et al., 2007; Van den Berg JM et al., 2009; Roos et al., 2010]. However, the sister, the mother, and the maternal grandmother had phagocyte profiles characteristic of CYBB wt/wt individuals (see above), and these homogenous profiles were not caused by skewed X-chromosome inactivation, as assessed by an HUMARA assay. "
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    ABSTRACT: Retrotransposon-mediated insertion of a LINE-1 or an Alu element into a human gene is a well known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X chromosome. In a Dutch male patient with chronic granulomatous disease a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense polyA tail, target site duplication and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA. This article is protected by copyright. All rights reserved.
    Full-text · Article · Apr 2014 · Human Mutation
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