title: Molecular quality control machinery contributes to the leukocyte NADPH oxidase deficiency in chronic granulomatous disease.
abstract: Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by defects in leukocyte NADPH oxidase. Various inherited defects in one of the membrane-bound components of NADPH oxidase, gp91-phox, cause X-linked (X91) CGD. Analysis of three patients with X91 CGD revealed that different mechanisms of molecular quality control lead to the common phenotype of absence of mature membrane-bound NADPH oxidase complex in leukocytes. In the first patient, aberrant intron splicing created a premature stop codon. However, the mutant mRNA was degraded prematurely, which prevented the production of truncated protein. In the second patient, a frameshift mutation with the potential to generate a gp91-phox polypeptide, with an aberrant and elongated C-terminus, led to barely detectable levels of gp91-phox, even though the reported functional domains of the protein appeared unaffected. In the third patient, a point mutation created a single amino acid change in the predicted FAD-binding site of gp91-phox. Although gp91-phox was detectable with Western blotting, no cytochrome b(558) was expressed on the cell surface. These analyses showed that molecular quality control machinery plays an important role in the pathogenesis of CGD, not only in the X910 but also in the X91- form of this X-linked disease.
authors: Department of Pediatrics, National Cheng-Kung University, 138 Sheng-Li Rd, Tainan 704, Taiwan.
authors: Shio-Jean
authors: SJ
authors: Lin
authors: Ya-Fang
authors: YF
authors: Huang
authors: Jing-Yi
authors: JY
authors: Chen
authors: Paul G
authors: PG
authors: Heyworth
authors: Deborah
authors: D
authors: Noack
authors: Ji-Yao
authors: JY
authors: Wang
authors: Ching-Yuan
authors: CY
authors: Lin
authors: Bor-Luen
authors: BL
authors: Chiang
authors: Chin-Mu
authors: CM
authors: Yang
authors: Ching-Chuan
authors: CC
authors: Liu
authors: Chi-Chang
authors: CC
authors: Shieh
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology; D003573:Cytochrome b Group / Q000032:analysis / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006105:Granulomatous Disease, Chronic / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007223:Infant; D007425:Intracellular Membranes / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency* / Q000378:metabolism; D017354:Point Mutation; D011786:Quality Control; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
chemical_list: D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C036888:cytochrome b558; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases