A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity.
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.
Matute
Juan D
JD
Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Arias
Andres A
AA
Wright
Nicola A M
NA
Wrobel
Iwona
I
Waterhouse
Christopher C M
CC
Li
Xing Jun
XJ
Marchal
Christophe C
CC
Stull
Natalie D
ND
Lewis
David B
DB
Steele
MacGregor
M
Kellner
James D
JD
Yu
Weiming
W
Meroueh
Samy O
SO
Nauseef
William M
WM
Dinauer
Mary C
MC
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
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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