title: 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.
abstract: 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.
authors.affiliation: Centre Diagnostic et Recherche sur la Granulomatose Septique CGD, Laboratoire TIMC-IMAG, UMR CNRS 5525, Université Joseph Fourier, CHU Grenoble, BP 217, 38043 Grenoble Cedex 9, France.
authors.forename: Federica
authors.initials: F
authors.lastname: Defendi
authors.forename: Eva
authors.initials: E
authors.lastname: Decleva
authors.forename: Cécile
authors.initials: C
authors.lastname: Martel
authors.forename: Pietro
authors.initials: P
authors.lastname: Dri
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Stasia
mesh_terms: D001483:Base Sequence; D041321:Chromosomes, Human, X / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007558:Italy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016415:Sequence Alignment; D013481:Superoxides / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D016877:Oxidants; D013481:Superoxides; D006861:Hydrogen Peroxide; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases