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The search for a genetic defect in Polish patients with chronic granulomatous disease

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Jurkowska M., Kurenko-Deptuch M., Bal J., Roos D.

Archivum Immunologiae et Therapiae Experimentalis

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2004

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vol. 52

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issue 6

441-446

EN

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytic cells are unable to generate superoxide anions. Patients with CGD are predisposed to recurrent bacterial and fungal infections because the superoxide-generating NADPH oxidase activity is needed for efficient killing of microbes. Among the at least 5 subunits creating a functional NADPH oxidase, a molecular defect located in any of the gp91phox, p22phox, p47phox, or p67phox subunits may cause CGD. In this study, 8 patients were diagnosed with CGD on the basis of clinical findings and absence of nitroblue tetrazolium reduction in phagocytes. Southern blot analysis, GeneScan, and direct sequencing were performed to define particular DNA mutations. Among 6 X-linked CGD (X-CGD) patients, 4 different mutations were identified in the X- -linked CYBB gene (encoding gp91phox) by direct sequencing. A novel missense mutation, located in the NADPH-binding region of gp91phox, was found in 2 brothers. One frameshift 1578delA, one splicing 252G->A mutation, and one partial gene deletion were also identified. The molecular defect in the NCF1 gene (encoding p47phox) was established in 2 patients. One was a .GT/.GT homozygote, the other carried, besides this GT deletion on one allele, a unique Phe118stop mutation on the other. In general, the X-CGD patients within the group followed a more severe clinical course than the patients with an NCF1 defect. However, the lack of a straightforward genotype- -phenotype correlation indicates that the clinical severity of CGD depends also on other antimicrobial host-defense systems.

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Genetic and biochemical background of chronic granulomatous disease

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Jurkowska M., Bernatowska E., Bal J.

Archivum Immunologiae et Therapiae Experimentalis

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2004

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vol. 52

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issue 2

113-120

EN

Chronic granulomatous disease (CGD) is a rare inherited immunodeficency 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 (gp91phox, p22phox, p47phox and p67phox) 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 gp91phox. 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 .GT 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.

3

Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses

100%

El-Benna J., Dang P. M.-C., Gougerot-Pocidalo A.-M., Elbim C.

Archivum Immunologiae et Therapiae Experimentalis

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2005

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vol. 53

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issue 3

199-206

EN

Phagocytes such as neutrophils and monocytes play an essential role in host defenses against microbial pathogens. Reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, the hydroxyl radical, and hypochlorous acid, together with microbicidal peptides and proteases, constitute their antimicrobial arsenal. The enzyme responsible for superoxide anion production and, consequently, ROS generation, is called NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of cytosolic proteins (p47phox, p67phox, p40phox, and rac1/2) and membrane proteins (p22phox and gp91phox, which form cytochrome b558) which assemble at membrane sites upon cell activation. The importance of this enzyme in host defenses is illustrated by a life-threatening genetic disorder called chronic granulomatous disease in which the phagocyte enzyme is dysfunctional, leading to life-threatening bacterial and fungal infections. Also, because ROS can damage surrounding tissues, their production, and thus NADPH oxidase activation, must be tightly regulated. This review describes the structure and activation of the neutrophil NADPH enzyme complex.

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3 Archivum Immunologiae et Therapiae Experimentalis

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2 2004

2 Bal J.

2 Jurkowska M.

1 Bernatowska E.

1 Dang P. M.-C.

1 El-Benna J.

1 Elbim C.

1 Gougerot-Pocidalo A.-M.

1 Kurenko-Deptuch M.

1 Roos D.

The search for a genetic defect in Polish patients with chronic granulomatous disease

Genetic and biochemical background of chronic granulomatous disease

Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses