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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3309-3315. Prepublished online as a Blood First Edition Paper on August 19, 2009; DOI 10.1182/blood-2009-07-231498. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-07-231498v1 114/15/3309    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Matute, J. D. Articles by Dinauer, M. C. PubMed PubMed Citation Articles by Matute, J. D. Articles by Dinauer, M. C. Related Collections Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity Juan D. Matute1,*, Andres A. Arias1,*, Nicola A. M. Wright2, Iwona Wrobel2, Christopher C. M. Waterhouse2, Xing Jun Li1, Christophe C. Marchal1, Natalie D. Stull1, David B. Lewis3, MacGregor Steele2, James D. Kellner2,4, Weiming Yu5, Samy O. Meroueh6, William M. Nauseef7, and Mary C. Dinauer1,8 1 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis; 2 Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, AB; 3 Department of Pediatrics and Program in Immunology, Stanford University School of Medicine, CA; 4 Departments of Microbiology and Infectious Disease, and Community of Health Sciences, and 5 Department of Pathology, Alberta Children's Hospital, University of Calgary, Calgary, AB; 6 Departments of Biochemistry and Molecular Biology, and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis; 7 Inflammation Program, Department of Medicine, Veterans Administration Medical Center Iowa City, and Roy J. and Lucille A. Carver College of Medicine, University of Iowa; and 8 Departments of Microbiology/Immunology, and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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