Details

Autor(en) / Beteiligte

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

Titel

A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Ist Teil von

• Blood, 2009-10, Vol.114 (15), p.3309-3315

Ort / Verlag

Washington, DC: Elsevier Inc

Erscheinungsjahr

2009

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 gp91phox and p22phox, which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47phox and p67phox. A fifth subunit, p40phox, 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 p40phox, 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. p40phoxR105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40phox-deficient granulocytes, with premature loss of p40phoxR105Q from phagosomes. Thus, p40phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.