Hematologically Important Mutations: X-Linked Chronic Granulomatous Disease—An Update

Roos, Dirk; Kuhns, Douglas B.; Maddalena, Anne; Roesler, Joachim; López, Juan A.; Ariga, Tadashi; Avčin, Tadej; Boer, Martin de; Bustamante, Jacinta; Condino‐Neto, Antônio; Matteo, Gigliola Di; He, Jianxin; Hill, Harry R.; Holland, Steven M.; Kannengiesser, Caroline; Köker, Mustafa Yavuz; Kondratenko, Irina; Leeuwen, Karin van; Malech, Harry L.; Maródi, László; Nunoi, Hiroyuki; Stasia, Marie José; Ventura, Anna Maria; Witwer, Carl T.; Wolach, Baruch; Gallin, John I.

doi:10.1006/bcmd.1997.0163

Cited by 108 publications

(8 citation statements)

References 97 publications

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“…The mutation in this patient is unusual, because in general the mutations in CYBB are either point mutations (substitutions, deletions, or insertions) or larger insertions or deletions. 32 However, occasionally, more complicated mutations are found. Since CYBB is on the X chromosome, CGD patients with mutations in this gene are usually male, but a few female patients are known.…”

Section: Discussionmentioning

confidence: 99%

“…Since CYBB is on the X chromosome, CGD patients with mutations in this gene are usually male, but a few female patients are known. 1,6,32 Until now, these all are heterozygotes for CYBB mutations with a low number of functionally active neutrophils (Ͻ 15%). This is caused by skewed X-chromosome inactivation, which is a random process early in the fetal development of female individuals.…”

Section: Discussionmentioning

confidence: 99%

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Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Wolach

Scharf

Gavrieli

et al. 2005

Blood

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Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91 phox , a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG [90][91][92] 3 GGT), predicting Tyr30Arg31 3 stop, Val in gp91 phox , who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her Xchromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow. IntroductionChronic granulomatous disease (CGD) is a rare, heterogeneous, inherited disorder that affects about 1 in 250 000 individuals. 1,2 The main defect in CGD is a failure of neutrophils, monocytes, macrophages, and eosinophils to mount a respiratory burst and, therefore, to generate superoxide anions and other reactive oxygen species derived from superoxide, such as hydrogen peroxide. This renders the patients susceptible to severe, recurrent bacterial and fungal infections. [3][4][5] The enzyme that generates superoxide is a phagocyte-specific nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, consisting of 2 membrane-bound subunits and 4 cytosolic proteins involved in activity regulation of the enzyme. 1,2 The central, catalytic subunit is gp91 phox , a flavocytochrome that forms a heterodimer with p22 phox in the plasma membrane of phagocytic leukocytes. Defects in gp91 phox are inherited in an X-linked fashion because its gene, CYBB, is located on the X chromosome. About 70% to 75% of the CGD patients are X-CGD patients. 1,2,6 Autosomal forms of CGD are due to mutations in CYBA, the gene that encodes p22 phox in approximately 3% of the CGD patients 6,7 or to mutations in the genes encoding the cytosolic proteins p47 phox (ϳ 25%) or p67 phox (ϳ 3%). 1,2,6 For many years the onset of CGD was regarded to occur early in infancy, with fatal outcome in adolescence, due to the recurrent severe infections and the secondary granulomatous and fibrotic tissue formation that develops in many organs. Changes frequently occur in the skin, lymph nodes, and lungs, but also in bones, joints, liver, and kidneys, leading eventually to pulmonary, gastrointestinal, musculoskeletal, and renal insufficiency. 1,2,5,8,9 In the last decades, with the rapid developme...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Wolach

Scharf

Gavrieli

et al. 2005

Blood

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“…Although precise definition of the topology of tlavocytochrome b55x is incomplete, a great deal of functional information has been deduced from structure-function analyses of PMNs from subjects whose mutation in the cytochrome subunits has been defined at the molecular level (26)(27)(28)(29).…”

Section: Flavocytochrome Bsssmentioning

confidence: 99%

The NADPH‐Dependent Oxidase of Phagocytes

Nauseef

1999

Proc Assoc American Phys

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Polymorphonuclear leukocytes (PMNs) represent a prominent cellular element in the innate immune system, serving to ingest exogenous particles and microbes and to kill phagocytosed microorganisms. The microbicidal activity of PMNs depends on the interactions of a broad array of potent systems, including relatively stable degradative proteins as well as labile reactive radicals. These systems can be categorized as oxygen-dependent and nonoxidative mechanisms, although the physiologically relative activity depends on the precisely orchestrated interplay between both systems. The enzyme complex responsible for the activity of the oxygen-dependent system is the respiratory burst oxidase and its important contribution to host defense is best illustrated by the frequent and severe infections seen in individuals whose PMNs lack oxidase activity, namely patients with chronic granulomatous disease (CGD). Multiple elements comprise the oxygen-dependent system, and significant advances have been made in the past decade in understanding the protein components of the respiratory burst oxidase, their subcellular distribution in resting PMNs, and their agonist-dependent assembly into a functional system at phagosomal and plasma membranes. In parallel, substantial insights into the molecular bases of CGD have likewise been made. Nonetheless there remain significant gaps in our understanding of the precise functional contributions of particular components of the system, the molecular mechanisms that regulate their coordinated assembly, and the role of related proteins in nonphagocytic cells.

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“…The type of mutation that causes both types of CGD is varied and may be deletions, frame-shift, nonsense, and missense. 18,19 A. B.…”

Section: Discussionmentioning

confidence: 99%

Chronic Granulomatous Disease: A Rare Hereditary Immuno-deficiency Disorder in a Young Boy with Its Adverse Consequences

Rashid

Nigar

Hassan

2016

J. Bangladesh Coll. Phys.

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Summary:Chronic granulomatous disease (CGD) is a primary immunodeficiency disease which results from absence of the NADPH oxidase in the professional phagocytic cells neutrophils, monocytes, macrophages and eosinophils. Deficiency of this oxidase renders the patient liable to infection by bacteria and fungi, and, as the name of the disease suggests, to chronic granulomatous inflammation. Here, a young boy presented with increasing breathlessness and productive cough had recurrent episode of pulmonary infection since his childhood. Repeated Chest X-ray and CT scan showed homogenous opacities at different places of lung in different occasions with bilateral reticulo-nodular opacities. Mulipleoraganisms were isolated from sputum at different times. A nitroblu-tetrazolium test (NBT) was done abroad which was positive and confirmed his diagnosis. Since then, He had prophylactic fluconazol and sulphamethoxazoltrimethoprime daily and pneumocaccal and influenza vaccination regularly and proper treatment of acute infective episodes accordingly. In spite all these measures, repeated infection caused grievous harm to his lung leading to irreversible pulmonary fibrosis and bronchiectasis. As a consequence, he became home bound, oxygen dependant and dependant on regular use of long acting bronchodilators in different form. Hematopoeitic stem cell transplantation was advised which was not affordable for his parents. Now, this young boy is waiting for further assaults to his lungs and further deterioration and ultimate hopeless outcomes.

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Hematologically Important Mutations: X-Linked Chronic Granulomatous Disease—An Update

Cited by 108 publications

References 97 publications

Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

The NADPH‐Dependent Oxidase of Phagocytes

Chronic Granulomatous Disease: A Rare Hereditary Immuno-deficiency Disorder in a Young Boy with Its Adverse Consequences

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