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Inherited p40^{phox} deficiency differs from classic chronic granulomatous disease

van de Geer, A; Nieto-Patlán, A; Kuhns, DB; Tool, ATJ; Arias, AA; Bouaziz, M; de Boer, M; ... Bustamante, J; + view all (2018) Inherited p40^{phox} deficiency differs from classic chronic granulomatous disease. The Journal of Clinical Investigation , 128 (9) pp. 3957-3975. 10.1172/JCI97116. Green open access

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Abstract

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40^{phox} subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40^{phox}-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 p40^{phox} deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Type: Article
Title: Inherited p40^{phox} deficiency differs from classic chronic granulomatous disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI97116
Publisher version: https://doi.org/10.1172/JCI97116
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Genetics, Immunology, Inflammatory bowel disease, Macrophages, Neutrophils
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10056669
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