title: Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease.
abstract: Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and so cannot generate superoxide anions (O(2) (-)). The most common form is caused by mutations in CYBB encoding gp91 phox, the heavy chain of flavocytochrome b(558) (XCGD). We investigated 11 male patients and their families suspected of suffering from X-linked CGD. These XCGD patients were classified as having different variants (X91(0), X91(-) or X91(+)) according to their cytochrome b(558) expression and NADPH oxidase activity. Nine patients had X91(0) CGD, one had X91(-) CGD and one had X91(+) CGD. Six mutations in CYBB were novel. Of the four new X91(0) CGD cases, three were point mutations: G65A in exon 2, G387T in exon 5 and G970T in exon 9, leading to premature stop codons at positions Try18, Try125 and Glu320, respectively, in gp91 phox. One case of X91(0) CGD originated from a new 1005G deletion detected in exon 9. Surprisingly, four nonsense mutations in exon 5 led to the generation of two mRNAs, one with a normal size containing the mutation and the other in which exon 5 had been spliced. A novel X91(-) CGD case with low gp91 phox expression was diagnosed. It was caused by an 11-bp deletion in the linking region between exon 12 and intron 12, activating a new cryptic site. Finally, a new X91(+) CGD case was detected, characterized by a missense mutation Leu505Arg in the potential NADPH-binding site of gp91 phox. No clear correlation between the severity of the clinical symptoms and the sub-type of XCGD could be established.
authors.affiliation: Laboratoire d'Enzymologie, GREPI EA 2938 UJF, CHU 38043, Grenoble Cedex 9, France. MJStasia@chu-grenoble.fr
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Stasia
authors.forename: Pierre
authors.initials: P
authors.lastname: Bordigoni
authors.forename: Daniel
authors.initials: D
authors.lastname: Floret
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Brion
authors.forename: Cécile
authors.initials: C
authors.lastname: Bost-Bru
authors.forename: Gérard
authors.initials: G
authors.lastname: Michel
authors.forename: Pierre
authors.initials: P
authors.lastname: Gatel
authors.forename: Denis
authors.initials: D
authors.lastname: Durant-Vital
authors.forename: Marie Antoinette
authors.initials: MA
authors.lastname: Voelckel
authors.forename: Xing Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: Michèle
authors.initials: M
authors.lastname: Guillot
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Maquet
authors.forename: Cécile
authors.initials: C
authors.lastname: Martel
authors.forename: Françoise
authors.initials: F
authors.lastname: Morel
mesh_terms: D005838:Genotype; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D008562:Membrane Glycoproteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D013755:Tetradecanoylphorbol Acetate