title: A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.
abstract: Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91(phox) and p22(phox), which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47(phox) and p67(phox). A fifth subunit, p40(phox), plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40(phox), in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40(phox)R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40(phox)-deficient granulocytes, with premature loss of p40(phox)R105Q from phagosomes. Thus, p40(phox) binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.
authors.affiliation: Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Matute
authors.forename: Andres A
authors.initials: AA
authors.lastname: Arias
authors.forename: Nicola A M
authors.initials: NA
authors.lastname: Wright
authors.forename: Iwona
authors.initials: I
authors.lastname: Wrobel
authors.forename: Christopher C M
authors.initials: CC
authors.lastname: Waterhouse
authors.forename: Xing Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: Christophe C
authors.initials: CC
authors.lastname: Marchal
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Stull
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
authors.forename: MacGregor
authors.initials: M
authors.lastname: Steele
authors.forename: James D
authors.initials: JD
authors.lastname: Kellner
authors.forename: Weiming
authors.initials: W
authors.lastname: Yu
authors.forename: Samy O
authors.initials: SO
authors.lastname: Meroueh
authors.forename: William M
authors.initials: WM
authors.lastname: Nauseef
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002273:Carcinogens; D045744:Cell Line, Tumor; D002648:Child; D018388:Codon, Terminator; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D030342:Genetic Diseases, Inborn / Q000201:enzymology* / Q000235:genetics*; D006105:Granulomatous Disease, Chronic / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D010587:Phagocytosis / Q000235:genetics; D010703:Phorbol Esters; D018129:Phosphatidylinositol Phosphates; D013481:Superoxides / Q000378:metabolism
chemical_list: D002273:Carcinogens; D018388:Codon, Terminator; D010703:Phorbol Esters; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases; C113333:NCF4 protein, human
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