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Inherited p40phox deficiency differs from classic chronic granulomatous disease

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-o...

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Published in:The Journal of clinical investigation 2018-08, Vol.128 (9), p.3957-3975
Main Authors: van de Geer, Annemarie, Nieto-Patlán, Alejandro, Kuhns, Douglas B, Tool, Anton Tj, Arias, Andrés A, Bouaziz, Matthieu, de Boer, Martin, Franco, José Luis, Gazendam, Roel P, van Hamme, John L, van Houdt, Michel, van Leeuwen, Karin, Verkuijlen, Paul Jh, van den Berg, Timo K, Alzate, Juan F, Arango-Franco, Carlos A, Batura, Vritika, Bernasconi, Andrea R, Boardman, Barbara, Booth, Claire, Burns, Siobhan O, Cabarcas, Felipe, Bensussan, Nadine Cerf, Charbit-Henrion, Fabienne, Corveleyn, Anniek, Deswarte, Caroline, Azcoiti, María Esnaola, Foell, Dirk, Gallin, John I, Garcés, Carlos, Guedes, Margarida, Hinze, Claas H, Holland, Steven M, Hughes, Stephen M, Ibañez, Patricio, Malech, Harry L, Meyts, Isabelle, Moncada-Velez, Marcela, Moriya, Kunihiko, Neves, Esmeralda, Oleastro, Matias, Perez, Laura, Rattina, Vimel, Oleaga-Quintas, Carmen, Warner, Neil, Muise, Aleixo M, López, Jeanet Serafín, Trindade, Eunice, Vasconcelos, Julia, Vermeire, Séverine, Wittkowski, Helmut, Worth, Austen, Abel, Laurent, Dinauer, Mary C, Arkwright, Peter D, Roos, Dirk, Casanova, Jean-Laurent, Kuijpers, Taco W, Bustamante, Jacinta
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cited_by cdi_FETCH-LOGICAL-c368t-e6a2aed45345e9fd579ff481adadd884218ebe9a5c5986aed7edd0f59af978c83
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container_issue 9
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container_title The Journal of clinical investigation
container_volume 128
creator van de Geer, Annemarie
Nieto-Patlán, Alejandro
Kuhns, Douglas B
Tool, Anton Tj
Arias, Andrés A
Bouaziz, Matthieu
de Boer, Martin
Franco, José Luis
Gazendam, Roel P
van Hamme, John L
van Houdt, Michel
van Leeuwen, Karin
Verkuijlen, Paul Jh
van den Berg, Timo K
Alzate, Juan F
Arango-Franco, Carlos A
Batura, Vritika
Bernasconi, Andrea R
Boardman, Barbara
Booth, Claire
Burns, Siobhan O
Cabarcas, Felipe
Bensussan, Nadine Cerf
Charbit-Henrion, Fabienne
Corveleyn, Anniek
Deswarte, Caroline
Azcoiti, María Esnaola
Foell, Dirk
Gallin, John I
Garcés, Carlos
Guedes, Margarida
Hinze, Claas H
Holland, Steven M
Hughes, Stephen M
Ibañez, Patricio
Malech, Harry L
Meyts, Isabelle
Moncada-Velez, Marcela
Moriya, Kunihiko
Neves, Esmeralda
Oleastro, Matias
Perez, Laura
Rattina, Vimel
Oleaga-Quintas, Carmen
Warner, Neil
Muise, Aleixo M
López, Jeanet Serafín
Trindade, Eunice
Vasconcelos, Julia
Vermeire, Séverine
Wittkowski, Helmut
Worth, Austen
Abel, Laurent
Dinauer, Mary C
Arkwright, Peter D
Roos, Dirk
Casanova, Jean-Laurent
Kuijpers, Taco W
Bustamante, Jacinta
description 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.
doi_str_mv 10.1172/jci97116
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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. 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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.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Alleles</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Female</subject><subject>Gene Knockout Techniques</subject><subject>Granulomatous Disease, Chronic - diagnosis</subject><subject>Granulomatous Disease, Chronic - genetics</subject><subject>Granulomatous Disease, Chronic - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Loss of Function Mutation</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutant Proteins - genetics</subject><subject>Mutant Proteins - metabolism</subject><subject>NADPH Oxidases - genetics</subject><subject>NADPH Oxidases - metabolism</subject><subject>Pedigree</subject><subject>Phagocytes - immunology</subject><subject>Phagocytes - metabolism</subject><subject>Phagocytes - microbiology</subject><subject>Phenotype</subject><subject>Phosphoproteins - deficiency</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Prognosis</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Transduction, Genetic</subject><subject>Young 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p40phox deficiency differs from classic chronic granulomatous disease</title><author>van de Geer, Annemarie ; Nieto-Patlán, Alejandro ; Kuhns, Douglas B ; Tool, Anton Tj ; Arias, Andrés A ; Bouaziz, Matthieu ; de Boer, Martin ; Franco, José Luis ; Gazendam, Roel P ; van Hamme, John L ; van Houdt, Michel ; van Leeuwen, Karin ; Verkuijlen, Paul Jh ; van den Berg, Timo K ; Alzate, Juan F ; Arango-Franco, Carlos A ; Batura, Vritika ; Bernasconi, Andrea R ; Boardman, Barbara ; Booth, Claire ; Burns, Siobhan O ; Cabarcas, Felipe ; Bensussan, Nadine Cerf ; Charbit-Henrion, Fabienne ; Corveleyn, Anniek ; Deswarte, Caroline ; Azcoiti, María Esnaola ; Foell, Dirk ; Gallin, John I ; Garcés, Carlos ; Guedes, Margarida ; Hinze, Claas H ; Holland, Steven M ; Hughes, Stephen M ; Ibañez, Patricio ; Malech, Harry L ; Meyts, Isabelle ; Moncada-Velez, Marcela ; Moriya, Kunihiko ; Neves, Esmeralda ; Oleastro, Matias ; Perez, Laura ; Rattina, Vimel ; Oleaga-Quintas, Carmen ; Warner, Neil ; Muise, Aleixo M ; López, Jeanet Serafín ; Trindade, Eunice ; Vasconcelos, Julia ; Vermeire, Séverine ; Wittkowski, Helmut ; Worth, Austen ; Abel, Laurent ; Dinauer, Mary C ; Arkwright, Peter D ; Roos, Dirk ; Casanova, Jean-Laurent ; Kuijpers, Taco W ; Bustamante, Jacinta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c368t-e6a2aed45345e9fd579ff481adadd884218ebe9a5c5986aed7edd0f59af978c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Alleles</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Female</topic><topic>Gene Knockout Techniques</topic><topic>Granulomatous Disease, Chronic - diagnosis</topic><topic>Granulomatous Disease, Chronic - genetics</topic><topic>Granulomatous Disease, Chronic - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Loss of Function Mutation</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutant Proteins - genetics</topic><topic>Mutant Proteins - metabolism</topic><topic>NADPH Oxidases - genetics</topic><topic>NADPH Oxidases - metabolism</topic><topic>Pedigree</topic><topic>Phagocytes - immunology</topic><topic>Phagocytes - metabolism</topic><topic>Phagocytes - microbiology</topic><topic>Phenotype</topic><topic>Phosphoproteins - deficiency</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Prognosis</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Transduction, Genetic</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van de Geer, Annemarie</creatorcontrib><creatorcontrib>Nieto-Patlán, Alejandro</creatorcontrib><creatorcontrib>Kuhns, Douglas B</creatorcontrib><creatorcontrib>Tool, Anton Tj</creatorcontrib><creatorcontrib>Arias, Andrés 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(Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van de Geer, Annemarie</au><au>Nieto-Patlán, Alejandro</au><au>Kuhns, Douglas B</au><au>Tool, Anton Tj</au><au>Arias, Andrés A</au><au>Bouaziz, Matthieu</au><au>de Boer, Martin</au><au>Franco, José Luis</au><au>Gazendam, Roel P</au><au>van Hamme, John L</au><au>van Houdt, Michel</au><au>van Leeuwen, Karin</au><au>Verkuijlen, Paul Jh</au><au>van den Berg, Timo K</au><au>Alzate, Juan F</au><au>Arango-Franco, Carlos A</au><au>Batura, Vritika</au><au>Bernasconi, Andrea R</au><au>Boardman, Barbara</au><au>Booth, Claire</au><au>Burns, Siobhan O</au><au>Cabarcas, Felipe</au><au>Bensussan, Nadine Cerf</au><au>Charbit-Henrion, Fabienne</au><au>Corveleyn, Anniek</au><au>Deswarte, Caroline</au><au>Azcoiti, María Esnaola</au><au>Foell, Dirk</au><au>Gallin, John I</au><au>Garcés, Carlos</au><au>Guedes, Margarida</au><au>Hinze, Claas H</au><au>Holland, Steven M</au><au>Hughes, Stephen M</au><au>Ibañez, Patricio</au><au>Malech, Harry L</au><au>Meyts, Isabelle</au><au>Moncada-Velez, Marcela</au><au>Moriya, Kunihiko</au><au>Neves, Esmeralda</au><au>Oleastro, Matias</au><au>Perez, Laura</au><au>Rattina, Vimel</au><au>Oleaga-Quintas, Carmen</au><au>Warner, Neil</au><au>Muise, Aleixo M</au><au>López, Jeanet Serafín</au><au>Trindade, Eunice</au><au>Vasconcelos, Julia</au><au>Vermeire, Séverine</au><au>Wittkowski, Helmut</au><au>Worth, Austen</au><au>Abel, Laurent</au><au>Dinauer, Mary C</au><au>Arkwright, Peter D</au><au>Roos, Dirk</au><au>Casanova, Jean-Laurent</au><au>Kuijpers, Taco W</au><au>Bustamante, Jacinta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inherited p40phox deficiency differs from classic chronic granulomatous disease</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2018-08-31</date><risdate>2018</risdate><volume>128</volume><issue>9</issue><spage>3957</spage><epage>3975</epage><pages>3957-3975</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>29969437</pmid><doi>10.1172/jci97116</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0001-5664-6415</orcidid><orcidid>https://orcid.org/0000-0002-7754-8109</orcidid><orcidid>https://orcid.org/0000-0002-0801-0102</orcidid><orcidid>https://orcid.org/0000-0001-9624-3346</orcidid><orcidid>https://orcid.org/0000-0003-0665-1245</orcidid><orcidid>https://orcid.org/0000-0003-3207-5464</orcidid><orcidid>https://orcid.org/0000-0003-0765-9441</orcidid><orcidid>https://orcid.org/0000-0003-2578-4609</orcidid><orcidid>https://orcid.org/0000-0002-9207-5979</orcidid><orcidid>https://orcid.org/0000-0001-8861-4485</orcidid><orcidid>https://orcid.org/0000-0002-7411-5375</orcidid><orcidid>https://orcid.org/0000-0001-6803-7385</orcidid><orcidid>https://orcid.org/0000-0002-8668-6853</orcidid><orcidid>https://orcid.org/0000-0001-9247-4729</orcidid><orcidid>https://orcid.org/0000-0002-9478-8403</orcidid><orcidid>https://orcid.org/0000-0002-9510-6961</orcidid><orcidid>https://orcid.org/0000-0002-6057-0959</orcidid><orcidid>https://orcid.org/0000-0001-6038-7460</orcidid><orcidid>https://orcid.org/0000-0003-4615-3953</orcidid><orcidid>https://orcid.org/0000-0001-5874-5775</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0021-9738
ispartof The Journal of clinical investigation, 2018-08, Vol.128 (9), p.3957-3975
issn 0021-9738
1558-8238
language eng
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source PubMed (Medline); EZB Electronic Journals Library
subjects Adolescent
Adult
Alleles
Child
Child, Preschool
Female
Gene Knockout Techniques
Granulomatous Disease, Chronic - diagnosis
Granulomatous Disease, Chronic - genetics
Granulomatous Disease, Chronic - metabolism
HEK293 Cells
Humans
Loss of Function Mutation
Male
Middle Aged
Mutant Proteins - genetics
Mutant Proteins - metabolism
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Pedigree
Phagocytes - immunology
Phagocytes - metabolism
Phagocytes - microbiology
Phenotype
Phosphoproteins - deficiency
Phosphoproteins - genetics
Phosphoproteins - metabolism
Prognosis
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transduction, Genetic
Young Adult
title Inherited p40phox deficiency differs from classic chronic granulomatous disease
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