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: Juan D Matute, Andres A Arias, Nicola A M Wright, Iwona Wrobel, Christopher C M Waterhouse, Xing Jun Li, 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
• Journal: Blood (Blood) Vol. 114 Issue 15 Pg. 3309-15 (Oct 08 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19692703 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carcinogens
• Codon, Terminator
• Phorbol Esters
• Phosphatidylinositol Phosphates
• phosphatidylinositol 3-phosphate
• Superoxides
• N-Formylmethionine Leucyl-Phenylalanine
• NADPH Oxidases
• NCF4 protein, human

Topics

• Adult
• Amino Acid Substitution
• Carcinogens
• Cell Line, Tumor
• Child
• Codon, Terminator
• DNA Mutational Analysis
• Female
• Genes, Recessive
• Genetic Diseases, Inborn (enzymology, genetics)
• Granulomatous Disease, Chronic (enzymology, genetics, pathology)
• Heterozygote
• Humans
• Male
• Mutation, Missense
• N-Formylmethionine Leucyl-Phenylalanine (pharmacology)
• NADPH Oxidases (genetics, metabolism)
• Neutrophils (enzymology, pathology)
• Phagocytosis (genetics)
• Phorbol Esters
• Phosphatidylinositol Phosphates
• Superoxides (metabolism)