NADPH Oxidases pp 531-542 | Cite as

Chronic Granulomatous Disease

  • Dirk RoosEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1982)


Chronic granulomatous disease is a clinical condition that stems from inactivating mutations in NOX2 and its auxiliary proteins. Together, these proteins form the phagocyte NADPH oxidase enzyme that generates superoxide. Superoxide (O2ċ–) and its reduced product hydrogen peroxide (H2O2) give rise to several additional reactive oxygen species (ROS), which together are necessary for adequate killing of pathogens. Thus, CGD patients, with a phagocyte NADPH oxidase that is not properly functioning, suffer from recurrent, life-threatening infections with certain bacteria, fungi, and yeasts. Here, I give a short survey of the genetic mutations that underlie CGD, the effect of these mutations on the activity of the leukocyte NADPH oxidase, the clinical symptoms of CGD patients, and the treatment options for these patients.

Key words

Chronic granulomatous disease Phagocytes NADPH oxidase NOX2 Mutations CYBB CYBA NCF1 NCF2 NCF4 


  1. 1.
    Dinauer M, Newburger P, Borregaard N (2015) Phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orkin SH (eds) Hematology of infancy and childhood. Elsevier/Saunders, Philadelphia, pp 773–847Google Scholar
  2. 2.
    Nunes P, Demaurex N, Dinauer MC (2013) Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis. Traffic 14:1118–1131PubMedPubMedCentralGoogle Scholar
  3. 3.
    Van de Geer et al (2018) J Clin Invest 128:3957–3975Google Scholar
  4. 4.
    Roos D, Holland SM, Kuijpers TW (2014) Chronic granulomatous disease. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases, a molecular and genetic approach, 3rd edn. Oxford University Press, New York, pp 689–722Google Scholar
  5. 5.
    Alkhairy OK, Rezaei N, Graham RR et al (2015) RAC2 loss-of-function mutation in two siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol 135:1380–1384CrossRefGoogle Scholar
  6. 6.
    Roos D (2016) Chronic chranulomatous disease. Br Med Bull 118:53–66CrossRefGoogle Scholar
  7. 7.
    Kuhns DB, Alvord WG, Heller T et al (2010) Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 363:2600–2610CrossRefGoogle Scholar
  8. 8.
    Köker MY, Camcıoğlu Y, van Leeuwen K et al (2013) Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients. J Allergy Clin Immunol 132:1156–1163CrossRefGoogle Scholar
  9. 9.
    Wolach B, Gavrieli R, de Boer M et al (2017) Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients. Am J Hematol 92:28–36CrossRefGoogle Scholar
  10. 10.
    Leusen JH, Bolscher BG, Hilarius PM et al (1994) 156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox. J Exp Med 180:2329–2334CrossRefGoogle Scholar
  11. 11.
    Roos D, van Buul JD, Tool AT et al (2014) Two CGD families with a hypomorphic mutation in the activation domain of p67phox. J Clin Cell Immunol 5:pii:1000231Google Scholar
  12. 12.
    Cross AR, Curnutte JT (1995) The cytosolic activating factors p47-phox and p67-phox have distinct roles in the regulation of electron flow in NADPH oxidase. J Biol Chem 270:6543–6548CrossRefGoogle Scholar
  13. 13.
    Winkelstein JA, Marino MC, Johnston RB Jr et al (2000) Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 79:155–169CrossRefGoogle Scholar
  14. 14.
    Van den Berg JM, van Koppen E, Ahlin A et al (2009) Chronic granulomatous disease: the European experience. PLoS One 4:e5234CrossRefGoogle Scholar
  15. 15.
    Roos D, Tool AT, van Leeuwen K et al (2017) Biochemical and genetic diagnosis of chronic granulomatous disease. In: Seger R, Roos D, Segal B, Kuijpers TW (eds) Chronic granulomatous disease: genetics, biology and clinical management. Nova Publishers, New York, pp 231–300Google Scholar
  16. 16.
    Roos D, Kuhns DB, Maddalena A et al (2010) Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis 45:246–265CrossRefGoogle Scholar
  17. 17.
    de Boer M, van Leeuwen K, Geissler J et al (2014) Primary immunodeficiency caused by an exonized retroposed gene copy inserted in the CYBB gene. Hum Mutat 35:486–496CrossRefGoogle Scholar
  18. 18.
    De Boer M, van Leeuwen K, Geissler J et al (2017) Mutation in an exonic splicing enhancer site causing chronic granulomatous disease. Blood Cells Mol Dis 66:50–57CrossRefGoogle Scholar
  19. 19.
    Görlach A, Lee P, Roesler J et al (1997) A p47-phox pseudogene carries the most common mutation causing p47-phox deficient chronic granulomatous disease. J Clin Invest 100:1907–1918CrossRefGoogle Scholar
  20. 20.
    Hayrapetyan A, Dencher PC, van Leeuwen K et al (2013) Different unequal cross-over events between NCF1 and its pseudogenes in autosomal p47(phox)-deficient chronic granulomatous disease. Biochim Biophys Acta 1832:1662–1672CrossRefGoogle Scholar
  21. 21.
    Roos D, Kuhns DB, Maddalena A et al (2010) Hematologically important mutations: The autosomal recessive forms of chronic granulomatous disease (second update). Blood Cells Mol Dis 44:291–299CrossRefGoogle Scholar
  22. 22.
    De Boer M, Gavrieli R, van Leeuwen K et al (2018) A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews. J Med Genet 55:166–172PubMedGoogle Scholar
  23. 23.
    Matute JD, Arias AA, Wright NA et al (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 114:3309–3315CrossRefGoogle Scholar
  24. 24.
    Van Bruggen R, Bautista JM, Petropoulou T et al (2002) Deletion of leucine-61 in glucose-6-phosphate dehydrogenase leads to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 100:1026–1030CrossRefGoogle Scholar
  25. 25.
    De Boer M, Bolscher BGJM, Sijmons RH et al (1992) Prenatal diagnosis in a family with X-linked chronic granulomatous disease with the use of the polymerase chain reaction. Prenat Diagn 12:773–777CrossRefGoogle Scholar
  26. 26.
    De Boer M, Singh V, Dekker J et al (2002) Prenatal diagnosis in two families with autosomal, p47-phox-deficient chronic granulomatous disease due to a novel point mutation in NCF1. Prenat Diagn 22:235–240CrossRefGoogle Scholar
  27. 27.
    Rieber N, Hector A, Kuijpers TW et al (2012) Currents concepts of hyperinflammation in chronic granulomatous disease. Clin Dev Immunol 2012:252460CrossRefGoogle Scholar
  28. 28.
    Marciano BE, Rosenzweig SD, Kleiner DE et al (2004) Gastrointestinal involvement in chronic granulomatous disease. Pediatrics 114:462–468CrossRefGoogle Scholar
  29. 29.
    Magnani A, Brosselin P, Beauté J et al (2014) Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease. J Allergy Clin Immunol 134:655–662CrossRefGoogle Scholar
  30. 30.
    Marciano BE, Wesley R, De Carlo ES et al (2004) Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis 39:692–699CrossRefGoogle Scholar
  31. 31.
    Martire B, Rondelli R, Soresina A et al (2008) Clinical features, long-term follow-up and outcome of a large cohort of patients with chronic granulomatous disease: an Italian multicenter study. Clin Immunol 126:155–164CrossRefGoogle Scholar
  32. 32.
    Gűngőr T, Teira P, Slatter M et al (2014) Reduced intensity conditioning and HLA-matched haematopoietic stem-cell transplantation in patients with chronic granulomatous disease ; a prospective multicentre study. Lancet 383:436–448CrossRefGoogle Scholar
  33. 33.
    Morillo-Gutierrez B, Beier R, Rao K et al (2016) Treosulfan based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicentre experience. Blood 128:440–448CrossRefGoogle Scholar
  34. 34.
    Cole T, Pearce MS, Cant AJ et al (2013) Clinical outcome in children with chronic granulomatous disease managed conservatively or with hematopoietic stem cell transplantation. J Allergy Clin Immunol 132:1150–1155CrossRefGoogle Scholar
  35. 35.
    Ott MG, Seger R, Stein S et al (2007) Advances in the treatment of chronic granulomatous disease by gene therapy. Curr Gene Ther 7:155–161CrossRefGoogle Scholar
  36. 36.
    Stein S, Ott MG, Schultze-Strasser S et al (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 16:198–204CrossRefGoogle Scholar
  37. 37.
    Nakayama M (2010) Homologous recombination in human iPS and ES cells for use in gene correction therapy. Drug Discov Today 15:198–202CrossRefGoogle Scholar
  38. 38.
    Urnov FD, Rebar EJ, Holmes MC et al (2010) Genome editing with engineered zinc-finger nucleases. Nat Rev Genet 11:636–646CrossRefGoogle Scholar
  39. 39.
    Zou J, Sweeney CL, Chou BK et al (2011) Oxidase-deficient neutrophils from X-linked chronic granulomatous disease iPS cells: functional correction by zinc finger nuclease-mediated safe harbor targeting. Blood 117:5561–5572CrossRefGoogle Scholar
  40. 40.
    Mussolino C, Cathomen T (2012) TALE nucleases: tailored genome engineering made easy. Curr Opin Biotechnol 23:644–650CrossRefGoogle Scholar
  41. 41.
    Merling RK, Kuhns DB, Sweeney CL et al (2017) Gene-edited pseudogene resurrection corrects p47phox-deficient chronic granulomatous disease. Blood Adv 4:270–278CrossRefGoogle Scholar
  42. 42.
    Flynn R, Grundmann A, Renz P et al (2015) CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. Exp Hematol 43:838–848CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Sanquin Research, and Landsteiner Laboratory, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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