Skip to main content

Advertisement

SpringerLink
Log in

Novel NCF2 Mutation Causing Chronic Granulomatous Disease

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by defects in the NADPH oxidase complex. Mutations in NCF2 encoding the cytosolic factor p67phox result in autosomal recessive CGD. We describe three patients with a novel c.855G>C NCF2 mutation presenting with diverse clinical phenotype. Two siblings were heterozygous for the novel mutation and for a previously described exon 8–9 duplication, while a third unrelated patient was homozygous for the novel mutation. Mutation pathogenicity was confirmed by abnormal DHR123 assay and absent p67phox production and by sequencing of cDNA which showed abnormal RNA splicing. Clinically, the homozygous patient presented with suspected early onset interstitial lung disease and NCF2 mutation was found on genetic testing performed in search for surfactant-related defects. The two siblings also had variable presentation with one having history of severe pneumonia, lymphadenitis, and recurrent skin abscesses and the other presenting in his 30s with discoid lupus erythematosus and without significant infectious history. We therefore identified a novel pathogenic NCF2 mutation causing diverse and unusual clinical phenotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

CGD:

chronic granulomatous disease

NADPH oxidase:

nicotinamide adenine dinucleotide phosphate oxidase

ROS:

reactive oxygen species

Phox:

phagocyte oxidase

FTT:

failure to thrive

ILD:

interstitial lung disease

NCF:

neutrophil cytosolic factor

DHR:

dihydrorhodamine 123

PMA:

phorbol myristate acetate

fMLP:

N-formyl-L-methionyl-L-leucyl-L-phenylalanine

References

  1. Winkelstein JA, Marino MC, Johnston RB, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000;79(3):155–69. https://doi.org/10.1097/00005792-200005000-00003.

    Article  CAS  Google Scholar 

  2. van den Berg JM, van Koppen E, Ahlin A, et al. Chronic granulomatous disease: the European experience. PLoS One. 2009;4(4):e5234. https://doi.org/10.1371/journal.pone.0005234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973;52(3):741–4. https://doi.org/10.1172/JCI107236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reeves EP, Lu H, Jacobs HL, et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature. 2002;416(6878):291–7. https://doi.org/10.1038/416291a.

    Article  CAS  PubMed  Google Scholar 

  5. Holland SM. Chronic granulomatous disease. Hematol Oncol Clin North Am. 2013;27(1):89–99. https://doi.org/10.1016/j.hoc.2012.11.002.

    Article  PubMed  Google Scholar 

  6. Arnold DE, Heimall JR. A review of chronic granulomatous disease. Adv Ther. 2017;34(12):2543–57. https://doi.org/10.1007/s12325-017-0636-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wolach B, Gavrieli R, de Boer M, et al. Chronic granulomatous disease: clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients. Am J Hematol. 2017;92(1):28–36. https://doi.org/10.1002/ajh.24573.

    Article  CAS  PubMed  Google Scholar 

  8. Henrickson SE, Jongco AM, Thomsen KF, Garabedian EK, Thomsen IP. Noninfectious manifestations and complications of chronic granulomatous disease. J Pediatric Infect Dis Soc. 2018;7(suppl_1):S18–24. https://doi.org/10.1093/jpids/piy014.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Magnani A, Brosselin P, Beaute J, et al. Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease. J Allergy Clin Immunol. 2014;134(3):655–662.e8. https://doi.org/10.1016/j.jaci.2014.04.014.

    Article  PubMed  Google Scholar 

  10. Belambri SA, Rolas L, Raad H, Hurtado-Nedelec M, Dang PM, El-Benna J. NADPH oxidase activation in neutrophils: role of the phosphorylation of its subunits. Eur J Clin Invest. 2018;48(Suppl 2):e12951. https://doi.org/10.1111/eci.12951.

    Article  CAS  PubMed  Google Scholar 

  11. Arnadottir GA, Norddahl GL, Gudmundsdottir S, et al. A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease. Nat Commun. 2018;9(1):4447–018. https://doi.org/10.1038/s41467-018-06964-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Koker MY, Camcioglu Y, van Leeuwen K, et al. Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients. J Allergy Clin Immunol. 2013;132(5):1156–1163.e5. https://doi.org/10.1016/j.jaci.2013.05.039.

    Article  CAS  PubMed  Google Scholar 

  13. Roos D. Chronic granulomatous disease. Br Med Bull. 2016;118(1):50–63. https://doi.org/10.1093/bmb/ldw009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363(27):2600–10. https://doi.org/10.1056/NEJMoa1007097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Koker MY, Sanal O, van Leeuwen K, et al. Four different NCF2 mutations in six families from Turkey and an overview of NCF2 gene mutations. Eur J Clin Invest. 2009;39(10):942–51. https://doi.org/10.1111/j.1365-2362.2009.02195.x.

    Article  CAS  PubMed  Google Scholar 

  16. AlKhater SA, Deswarte C, Casanova JL, Bustamante J. A novel variant in the neutrophil cytosolic factor 2 (NCF2) gene results in severe disseminated BCG infectious disease: a clinical report and literature review. Mol Genet Genomic Med. 2020:e1237. https://doi.org/10.1002/mgg3.1237.

  17. Wolach B, Gavrieli R, de Boer M, et al. Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. Clin Immunol. 2008;129(1):103–14. https://doi.org/10.1016/j.clim.2008.06.012.

    Article  CAS  PubMed  Google Scholar 

  18. Wolach B, Gavrieli R, de Boer M, et al. Analysis of chronic granulomatous disease in the Kavkazi population in Israel reveals phenotypic heterogeneity in patients with the same NCF1 mutation (c.579G>A). J Clin Immunol. 2018;38(2):193–203. https://doi.org/10.1007/s10875-018-0475-1.

    Article  CAS  PubMed  Google Scholar 

  19. Clawson CC, Repine JE. Quantitation of maximal bactericidal capability in human neutrophils. J Lab Clin Med. 1976;88(2):316–27.

    CAS  PubMed  Google Scholar 

  20. Roos D, de Boer M. Molecular diagnosis of chronic granulomatous disease. Clin Exp Immunol. 2014;175(2):139–49. https://doi.org/10.1111/cei.12202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Borgato L, Bonizzato A, Lunardi C, et al. A 1.1-kb duplication in the p67phox gene causes chronic granulomatous disease. Hum Genet. 2001;108(6):504–10. https://doi.org/10.1007/s004390100526.

  22. Semple TR, Ashworth MT, Owens CM. Interstitial lung disease in children made easier...well, almost. Radiographics. 2017;37(6):1679–703. https://doi.org/10.1148/rg.2017170006.

    Article  PubMed  Google Scholar 

  23. Moghtaderi M, Kashef S, Rezaei N. Interstitial lung disease in a patient with chronic granulomatous disease. Iran J Pediatr. 2012;22(1):129–33.

    PubMed  PubMed Central  Google Scholar 

  24. Kawai T, Watanabe N, Yokoyama M, et al. Interstitial lung disease with multiple microgranulomas in chronic granulomatous disease. J Clin Immunol. 2014;34(8):933–40. https://doi.org/10.1007/s10875-014-0089-1.

    Article  CAS  PubMed  Google Scholar 

  25. Liu H, Liu J, Li H, Peng Y, Zhao S. Mimicking hypersensitivity pneumonitis as an uncommon initial presentation of chronic granulomatous disease in children. Orphanet J Rare Dis. 2017;12(1):169–017. https://doi.org/10.1186/s13023-017-0719-9.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kim-Howard X, Sun C, Molineros JE, et al. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Hum Mol Genet. 2014;23(6):1656–68. https://doi.org/10.1093/hmg/ddt532.

    Article  CAS  PubMed  Google Scholar 

  27. Jacob CO, Eisenstein M, Dinauer MC, et al. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proc Natl Acad Sci U S A. 2012;109(2):E59–67. https://doi.org/10.1073/pnas.1113251108.

    Article  PubMed  Google Scholar 

  28. Roos D, van Buul JD, Tool AT, et al. Two CGD families with a hypomorphic mutation in the activation domain of p67(phox). J Clin Cell Immunol. 2014;5(3).

  29. De Ravin SS, Naumann N, Cowen EW, et al. Chronic granulomatous disease as a risk factor for autoimmune disease. J Allergy Clin Immunol. 2008;122(6):1097–103. https://doi.org/10.1016/j.jaci.2008.07.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Idit Lachover Roth, Pazit Salamon and Tal Freund contributed equally to this work.

Authors and Affiliations

  1. Allergy and Clinical Immunology Unit, Meir Medical Center, Kfar-Saba and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Idit Lachover Roth & Ronit Confino-Cohen

  2. The Herbert Mast Cell Disorders Center, Laboratory of Allergy and Clinical Immunology, Meir Medical Center, Kfar Saba, Israel

    Pazit Salamon & Irit Shefler

  3. Department of Medicine, Allergy and Clinical Immunology Unit, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, 6 Weizmann St, 64239, Tel Aviv, Israel

    Tal Freund & David Hagin

  4. Pediatric Pulmonary Institute and CF Center, Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel

    Yael Ben-David Gadot & Lea Bentur

  5. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    Yael Ben-David Gadot, Tova Hershkovitz, Suhair Hanna & Lea Bentur

  6. Pediatric Hemato-oncology and Bone Marrow Transplantation Department, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Szilvia Baron

  7. The Genetic Institute, Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel

    Tova Hershkovitz

  8. Departments of Pediatric Immunology, Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel

    Suhair Hanna

Authors
  1. Idit Lachover Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pazit Salamon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tal Freund
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yael Ben-David Gadot
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Szilvia Baron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tova Hershkovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irit Shefler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Suhair Hanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ronit Confino-Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lea Bentur
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. David Hagin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ILR, PS, TF, SB, TH, DH: neutrophil functional assay, flow cytometry studies, Sanger sequencing, manuscript preparation, and review. YBDG, IS, SH, RCC, LB: manuscript preparation and review.

Corresponding author

Correspondence to David Hagin.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 462 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roth, I.L., Salamon, P., Freund, T. et al. Novel NCF2 Mutation Causing Chronic Granulomatous Disease. J Clin Immunol 40, 977–986 (2020). https://doi.org/10.1007/s10875-020-00820-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-020-00820-8

Keywords

Search

Navigation