TY - JOUR
T1 - Inherited p40 phox 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, Séverine
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
N1 - Funding Information:
The authors thank all the patients and their relatives as well as the treatment teams for their participation in this study. We also thank Céline Desvallées, Dominick Papandrea, Cécile Patissier, and Yelena Nemirovskaya at the HGMI laboratory (Rockefeller University branch) and the Institute Imagine branch for administrative assistance. We thank all the members of the Blood Cell Research Department and the HGMI Laboratory for helpful discussions. We acknowledge the use of the biological resources of the Imagine Institute DNA-Biobank (BB-33-00065). AVDG was supported by the Sanquin Blood Supply Product and Pro- cess Development Cellular Products Fund (PPOC 1957). ANP was supported by the CONACYT National PhD Fellowship Program. The HGMI Laboratory was funded in part by the NIAID (5R01AI089970 and 5R37AI095983), the National Center for Research Resources, and the National Center for Advancing Sciences of the NIH (8UL1TR000043), The Rockefeller University, the St. Giles Foundation, INSERM, Paris Descartes University, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), and the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10IAHU-01, to the Imagine Institute), ANR-IFNPHOX/ANR-13-ISV3-0001-01, and ANR-GENMS-MD/ANR-16-CE17-0005-01 (to JB), ECOSNord-C14S01 (to JB and JLF), and COLCIENCIAS (576-2013:111556934990, to JLF). KM was supported by a Japan Foundation for Pediatric Research fellowship grant. AMM was funded by the Canadian Institutes of Health Research (CIHR) and The Leona M. and Harry B. Helms-ley Charitable Trust. This work was supported in part by the Division of Intramural Research, NIAID, NIH and was funded in part with federal funds from the National Cancer Institute, NIH (HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/8/31
Y1 - 2018/8/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052571719&partnerID=8YFLogxK
U2 - 10.1172/JCI97116
DO - 10.1172/JCI97116
M3 - Article
C2 - 29969437
AN - SCOPUS:85052571719
SN - 0021-9738
VL - 128
SP - 3957
EP - 3975
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -