TY - JOUR
T1 - Inherited p40phox deficiency differs from classic chronic granulomatous disease
AU - van de Geer, Annemarie
AU - Nieto-Patlán, Alejandro
AU - Kuhns, Douglas B.
AU - Tool, Anton T. J.
AU - Arias, Andrés A.
AU - Bouaziz, Matthieu
AU - de Boer, Martin
AU - Franco, José Luis
AU - Gazendam, Roel P.
AU - van Hamme, John L.
AU - van Houdt, Michel
AU - van Leeuwen, Karin
AU - Verkuijlen, Paul J. H.
AU - van den Berg, Timo K.
AU - Alzate, Juan F.
AU - Arango-Franco, Carlos A.
AU - Batura, Vritika
AU - Bernasconi, Andrea R.
AU - Boardman, Barbara
AU - Booth, Claire
AU - Burns, Siobhan O.
AU - Cabarcas, Felipe
AU - Bensussan, Nadine Cerf
AU - Charbit-Henrion, Fabienne
AU - Corveleyn, Anniek
AU - Deswarte, Caroline
AU - Azcoiti, María Esnaola
AU - Foell, Dirk
AU - Gallin, John I.
AU - Garcés, Carlos
AU - Guedes, Margarida
AU - Hinze, Claas H.
AU - Holland, Steven M.
AU - Hughes, Stephen M.
AU - Ibañez, Patricio
AU - Malech, Harry L.
AU - Meyts, Isabelle
AU - Moncada-Velez, Marcela
AU - Moriya, Kunihiko
AU - Neves, Esmeralda
AU - Oleastro, Matias
AU - Perez, Laura
AU - Rattina, Vimel
AU - Oleaga-Quintas, Carmen
AU - Warner, Neil
AU - Muise, Aleixo M.
AU - López, Jeanet Serafín
AU - Trindade, Eunice
AU - Vasconcelos, Julia
AU - Vermeire, S. verine
AU - Wittkowski, Helmut
AU - Worth, Austen
AU - Abel, Laurent
AU - Dinauer, Mary C.
AU - Arkwright, Peter D.
AU - Roos, Dirk
AU - Casanova, Jean-Laurent
AU - Kuijpers, Taco W.
AU - Bustamante, Jacinta
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85052571719&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29969437
U2 - https://doi.org/10.1172/JCI97116
DO - https://doi.org/10.1172/JCI97116
M3 - Article
C2 - 29969437
SN - 0021-9738
VL - 128
SP - 3957
EP - 3975
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 9
ER -