A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity

Juan D. Matute, Andres A. Arias, Nicola A.M. Wright, Iwona Wrobel, Christopher C.M. Waterhouse, Jun Li Xing, Christophe C. Marchal, Natalie D. Stull, David B. Lewis, MacGregor Steele, James D. Kellner, Weiming Yu, Samy O. Meroueh, William M. Nauseef, Mary C. Dinauer

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Abstract

Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous in-flammation, 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 phoxR105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40 phox- deficient granulocytes, with premature loss of p40 phoxR105Q 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.

Original languageEnglish
Pages (from-to)3309-3315
Number of pages7
JournalBlood
Volume114
Issue number15
DOIs
StatePublished - Nov 19 2009
Externally publishedYes

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    Matute, J. D., Arias, A. A., Wright, N. A. M., Wrobel, I., Waterhouse, C. C. M., Xing, J. L., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., & Dinauer, M. C. (2009). A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood, 114(15), 3309-3315. https://doi.org/10.1182/blood-2009-07-231498