Inherited p40phox deficiency differs from classic chronic granulomatous disease
Annemarie van de Geer, … , Taco W. Kuijpers, Jacinta Bustamante
Annemarie van de Geer, … , Taco W. Kuijpers, Jacinta Bustamante
Published July 3, 2018
Citation Information: J Clin Invest. 2018;128(9):3957-3975. https://doi.org/10.1172/JCI97116.
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Research Article Genetics Immunology

Inherited p40phox deficiency differs from classic chronic granulomatous disease

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.

Authors

Annemarie van de Geer, Alejandro Nieto-Patlán, Douglas B. Kuhns, Anton T.J. Tool, Andrés A. Arias, Matthieu Bouaziz, Martin de Boer, José Luis Franco, Roel P. Gazendam, John L. van Hamme, Michel van Houdt, Karin van Leeuwen, Paul J.H. Verkuijlen, Timo K. van den Berg, Juan F. Alzate, Carlos A. Arango-Franco, Vritika Batura, Andrea R. Bernasconi, Barbara Boardman, Claire Booth, Siobhan O. Burns, Felipe Cabarcas, Nadine Cerf Bensussan, Fabienne Charbit-Henrion, Anniek Corveleyn, Caroline Deswarte, María Esnaola Azcoiti, Dirk Foell, John I. Gallin, Carlos Garcés, Margarida Guedes, Claas H. Hinze, Steven M. Holland, Stephen M. Hughes, Patricio Ibañez, Harry L. Malech, Isabelle Meyts, Marcela Moncada-Velez, Kunihiko Moriya, Esmeralda Neves, Matias Oleastro, Laura Perez, Vimel Rattina, Carmen Oleaga-Quintas, Neil Warner, Aleixo M. Muise, Jeanet Serafín López, Eunice Trindade, Julia Vasconcelos, Séverine Vermeire, Helmut Wittkowski, Austen Worth, Laurent Abel, Mary C. Dinauer, Peter D. Arkwright, Dirk Roos, Jean-Laurent Casanova, Taco W. Kuijpers, Jacinta Bustamante

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Figure 1

Identification of NCF4 mutations.

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Identification of NCF4 mutations. (A) Pedigrees of 12 families showing a...
(A) Pedigrees of 12 families showing allele segregation. The index cases are indicated by an arrow, and “E?” indicates an unknown genotype. Black or white symbols represent individuals with or without clinical manifestations, respectively. Triangles represent pregnancies not carried to term. m, mutated. (B) Schematic diagram of the structure of the NCF4 gene and p40phox protein, consisting of 9 exons and 3 protein domains, respectively. Newly discovered and previously reported mutations of the NCF4 gene are noted according to their localization. Red asterisks indicate mutations previously reported by Matute et al. (26).