Inherited p40phox deficiency differs from classic chronic granulomatous disease
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.16/2297 |
Resumo: | 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. |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Inherited p40phox deficiency differs from classic chronic granulomatous diseaseGeneticsImmunologyInflammatory bowel diseaseMacrophagesNeutrophilsBiallelic 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.American Society for Clinical InvestigationRepositório Científico do Centro Hospitalar do Portovan de Geer, A.Nieto-Patlán, A.Kuhns, D.Tool, A.Arias, A.Bouaziz, M.de Boer, M.Franco, J.Gazendam, R.van Hamme, J.van Houdt, M.van Leeuwen, K.Verkuijlen, P.van den Berg, T.Alzate, J.Arango-Franco, C.Batura, V.Bernasconi, A.Boardman, B.Booth, C.Burns, S.Cabarcas, .Bensussan, N.Charbit-Henrion, F.Corveleyn, A.Deswarte, C.Azcoiti, M.Foell, D.Gallin, J.Garcés, C.Guedes, M.Hinze, C.Holland, S.Hughes, S.Ibañez, P.Malech, H.Meyts, I.Moncada-Velez, M.Moriya, K.Neves, E.Oleastro, M.Perez, L.Rattina, V.Oleaga-Quintas, C.Warner, N.Muise, A.López, J.Trindade, E.Vasconcelos, J.Vermeire, S.Wittkowski, H.Worth, A.Abel, L.Dinauer, M.Arkwright, P.Roos, D.Casanova, J.tKuijpers, T.Bustamante, J.2019-11-14T15:35:12Z2018-08-31T00:00:00Z2018-08-31T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2297engJ Clin Invest. 2018 Aug 31;128(9):3957-39750021-973810.1172/JCI97116info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-09-05T12:40:51ZPortal AgregadorONG |
dc.title.none.fl_str_mv |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
title |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
spellingShingle |
Inherited p40phox deficiency differs from classic chronic granulomatous disease van de Geer, A. Genetics Immunology Inflammatory bowel disease Macrophages Neutrophils |
title_short |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
title_full |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
title_fullStr |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
title_full_unstemmed |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
title_sort |
Inherited p40phox deficiency differs from classic chronic granulomatous disease |
author |
van de Geer, A. |
author_facet |
van de Geer, A. Nieto-Patlán, A. Kuhns, D. Tool, A. Arias, A. Bouaziz, M. de Boer, M. Franco, J. Gazendam, R. van Hamme, J. van Houdt, M. van Leeuwen, K. Verkuijlen, P. van den Berg, T. Alzate, J. Arango-Franco, C. Batura, V. Bernasconi, A. Boardman, B. Booth, C. Burns, S. Cabarcas, . Bensussan, N. Charbit-Henrion, F. Corveleyn, A. Deswarte, C. Azcoiti, M. Foell, D. Gallin, J. Garcés, C. Guedes, M. Hinze, C. Holland, S. Hughes, S. Ibañez, P. Malech, H. Meyts, I. Moncada-Velez, M. Moriya, K. Neves, E. Oleastro, M. Perez, L. Rattina, V. Oleaga-Quintas, C. Warner, N. Muise, A. López, J. Trindade, E. Vasconcelos, J. Vermeire, S. Wittkowski, H. Worth, A. Abel, L. Dinauer, M. Arkwright, P. Roos, D. Casanova, J.t Kuijpers, T. Bustamante, J. |
author_role |
author |
author2 |
Nieto-Patlán, A. Kuhns, D. Tool, A. Arias, A. Bouaziz, M. de Boer, M. Franco, J. Gazendam, R. van Hamme, J. van Houdt, M. van Leeuwen, K. Verkuijlen, P. van den Berg, T. Alzate, J. Arango-Franco, C. Batura, V. Bernasconi, A. Boardman, B. Booth, C. Burns, S. Cabarcas, . Bensussan, N. Charbit-Henrion, F. Corveleyn, A. Deswarte, C. Azcoiti, M. Foell, D. Gallin, J. Garcés, C. Guedes, M. Hinze, C. Holland, S. Hughes, S. Ibañez, P. Malech, H. Meyts, I. Moncada-Velez, M. Moriya, K. Neves, E. Oleastro, M. Perez, L. Rattina, V. Oleaga-Quintas, C. Warner, N. Muise, A. López, J. Trindade, E. Vasconcelos, J. Vermeire, S. Wittkowski, H. Worth, A. Abel, L. Dinauer, M. Arkwright, P. Roos, D. Casanova, J.t Kuijpers, T. Bustamante, J. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Centro Hospitalar do Porto |
dc.contributor.author.fl_str_mv |
van de Geer, A. Nieto-Patlán, A. Kuhns, D. Tool, A. Arias, A. Bouaziz, M. de Boer, M. Franco, J. Gazendam, R. van Hamme, J. van Houdt, M. van Leeuwen, K. Verkuijlen, P. van den Berg, T. Alzate, J. Arango-Franco, C. Batura, V. Bernasconi, A. Boardman, B. Booth, C. Burns, S. Cabarcas, . Bensussan, N. Charbit-Henrion, F. Corveleyn, A. Deswarte, C. Azcoiti, M. Foell, D. Gallin, J. Garcés, C. Guedes, M. Hinze, C. Holland, S. Hughes, S. Ibañez, P. Malech, H. Meyts, I. Moncada-Velez, M. Moriya, K. Neves, E. Oleastro, M. Perez, L. Rattina, V. Oleaga-Quintas, C. Warner, N. Muise, A. López, J. Trindade, E. Vasconcelos, J. Vermeire, S. Wittkowski, H. Worth, A. Abel, L. Dinauer, M. Arkwright, P. Roos, D. Casanova, J.t Kuijpers, T. Bustamante, J. |
dc.subject.por.fl_str_mv |
Genetics Immunology Inflammatory bowel disease Macrophages Neutrophils |
topic |
Genetics Immunology Inflammatory bowel disease Macrophages Neutrophils |
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. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-08-31T00:00:00Z 2018-08-31T00:00:00Z 2019-11-14T15:35:12Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.16/2297 |
url |
http://hdl.handle.net/10400.16/2297 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
J Clin Invest. 2018 Aug 31;128(9):3957-3975 0021-9738 10.1172/JCI97116 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
American Society for Clinical Investigation |
publisher.none.fl_str_mv |
American Society for Clinical Investigation |
dc.source.none.fl_str_mv |
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instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
|
repository.mail.fl_str_mv |
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1777301182713167872 |