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J Clin Invest. 2018 Aug 31;128(9):3957-3975. doi: 10.1172/JCI97116. Epub 2018 Aug 6.

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

Author information

1
Department of Blood Cell Research, Sanquin Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
2
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
3
Paris Descartes University, Imagine Institute, Paris, France.
4
Department of Immunology, National School of Biological Science, National Polytechnic Institute, ENCB - IPN, Mexico.
5
Neutrophil Monitoring Laboratory, Clinical Services Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
6
Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, and.
7
School of Microbiology, University of Antioquia, Medellin, Colombia.
8
Department of Molecular Cell Biology and Immunology, VU Medical Center, VU University, Amsterdam, Netherlands.
9
National Center for Genomic Sequencing - CNSG-SIU, School of Medicine, University of Antioquia, Medellin, Colombia.
10
Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
11
Service of Immunology and Rheumatology, Garrahan National Pediatric Hospital, Buenos Aires, Argentina.
12
Department of Pediatric Allergy and Immunology, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom.
13
Department of Immunology, Great Ormond Street Hospital, NHS Foundation Trust, London, United Kingdom.
14
Institute of Immunity and Transplantation, University College London, London, United Kingdom.
15
Department of Clinical Immunology, Royal Free London, NHS Foundation Trust, London, United Kingdom.
16
SISTEMIC Group, Electronic Engineering Department, University of Antioquia, Medellin, Colombia.
17
Laboratory of Intestinal Immunity, INSERM U1163, Imagine Institute, Paris, France.
18
GENIUS group (GENetically ImmUne-mediated enteropathieS) of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).
19
Paris Descartes University, Paris, France.
20
Pediatric Gastroenterology, Hepatology and Nutrition Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
21
Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
22
Department of Immunology, Ricardo Gutierrez Children's Hospital, Buenos Aires, Argentina.
23
Department of Pediatric Rheumatology and Immunology, Munster University Hospital, Munster, Germany.
24
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
25
Department of Pediatrics, Santo Antonio Hospital, Porto, Portugal.
26
Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
27
Inflammatory Bowel Disease Program, Gastroenterology Department, Clinic Las Condes Medical Center, University of Chile, Santiago de Chile, Chile.
28
Department of Pediatric Hematology and Oncology and.
29
Department of Microbiology and Immunology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
30
Department of Immunology, Santo Antonio Hospital, Porto, Portugal.
31
SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, and.
32
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
33
Pediatric Gastroenterology Unit, Sao Joao Hospital, Porto, Portugal.
34
Division of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.
35
Department of Experimental Medicine, KU Leuven, Leuven, Belgium.
36
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
37
Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA.
38
Howard Hughes Medical Institute, New York, New York, USA.
39
Pediatric Hematology and Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
40
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Amsterdam, Netherlands.
41
Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
42
Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.

Abstract

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

KEYWORDS:

Genetics; Immunology; Inflammatory bowel disease; Macrophages; Neutrophils

PMID:
29969437
PMCID:
PMC6118590
DOI:
10.1172/JCI97116
[Indexed for MEDLINE]
Free PMC Article

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