Inherited p40                         phox                          deficiency differs from classic chronic granulomatous disease

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

doi:10.1172/JCI97116

Inherited p40 ^phox deficiency differs from classic chronic granulomatous disease

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 BoothSiobhan 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

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	3957-3975
Number of pages	19
Journal	Journal of Clinical Investigation
Volume	128
Issue number	9
DOIs	https://doi.org/10.1172/JCI97116
State	Published - Aug 31 2018

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10.1172/JCI97116

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Van De Geer, A., Nieto-Patlán, A., Kuhns, D. B., Tool, A. T. J., Arias, A. A., Bouaziz, M., De Boer, M., Franco, J. L., Gazendam, R. P., Van Hamme, J. L., Van Houdt, M., Van Leeuwen, K., Verkuijlen, P. J. H., Van Den Berg, T. K., Alzate, J. F., Arango-Franco, C. A., Batura, V., Bernasconi, A. R., Boardman, B., ... Bustamante, J. (2018). Inherited p40 ^phox deficiency differs from classic chronic granulomatous disease Journal of Clinical Investigation, 128(9), 3957-3975. https://doi.org/10.1172/JCI97116

@article{cca8e2ff1c8b4cdfb347cb5f0c663cfa,

title = " Inherited p40 phox deficiency differs from classic chronic granulomatous disease ",

abstract = " 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.",

author = "{Van De Geer}, Annemarie and Alejandro Nieto-Patl{\'a}n and Kuhns, {Douglas B.} and Tool, {Anton T.J.} and Arias, {Andr{\'e}s A.} and Matthieu Bouaziz and {De Boer}, Martin and Franco, {Jos{\'e} Luis} and Gazendam, {Roel P.} and {Van Hamme}, {John L.} and {Van Houdt}, Michel and {Van Leeuwen}, Karin and Verkuijlen, {Paul J.H.} and {Van Den Berg}, {Timo K.} and Alzate, {Juan F.} and Arango-Franco, {Carlos A.} and Vritika Batura and Bernasconi, {Andrea R.} and Barbara Boardman and Claire Booth and Burns, {Siobhan O.} and Felipe Cabarcas and Bensussan, {Nadine Cerf} and Fabienne Charbit-Henrion and Anniek Corveleyn and Caroline Deswarte and Azcoiti, {Mar{\'i}a Esnaola} and Dirk Foell and Gallin, {John I.} and Carlos Garc{\'e}s and Margarida Guedes and Hinze, {Claas H.} and Holland, {Steven M.} and Hughes, {Stephen M.} and Patricio Iba{\~n}ez and Malech, {Harry L.} and Isabelle Meyts and Marcela Moncada-Velez and Kunihiko Moriya and Esmeralda Neves and Matias Oleastro and Laura Perez and Vimel Rattina and Carmen Oleaga-Quintas and Neil Warner and Muise, {Aleixo M.} and L{\'o}pez, {Jeanet Seraf{\'i}n} and Eunice Trindade and Julia Vasconcelos and S{\'e}verine Vermeire and Helmut Wittkowski and Austen Worth and Laurent Abel and Dinauer, {Mary C.} and Arkwright, {Peter D.} and Dirk Roos and Casanova, {Jean Laurent} and Kuijpers, {Taco W.} and Jacinta Bustamante",

note = "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 C{\'e}line Desvall{\'e}es, Dominick Papandrea, C{\'e}cile 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: {\textcopyright} 2018 American Society for Clinical Investigation. All rights reserved.",

year = "2018",

month = aug,

day = "31",

doi = "10.1172/JCI97116",

language = "English",

volume = "128",

pages = "3957--3975",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

number = "9",

}

Van De Geer, A, Nieto-Patlán, A, Kuhns, DB, Tool, ATJ, Arias, AA, Bouaziz, M, De Boer, M, Franco, JL, Gazendam, RP, Van Hamme, JL, Van Houdt, M, Van Leeuwen, K, Verkuijlen, PJH, Van Den Berg, TK, Alzate, JF, Arango-Franco, CA, Batura, V, Bernasconi, AR, Boardman, B, Booth, C, Burns, SO, Cabarcas, F, Bensussan, NC, Charbit-Henrion, F, Corveleyn, A, Deswarte, C, Azcoiti, ME, Foell, D, Gallin, JI, Garcés, C, Guedes, M, Hinze, CH, Holland, SM, Hughes, SM, Ibañez, P, Malech, HL, Meyts, I, Moncada-Velez, M, Moriya, K, Neves, E, Oleastro, M, Perez, L, Rattina, V, Oleaga-Quintas, C, Warner, N, Muise, AM, López, JS, Trindade, E, Vasconcelos, J, Vermeire, S, Wittkowski, H, Worth, A, Abel, L, Dinauer, MC, Arkwright, PD, Roos, D, Casanova, JL, Kuijpers, TW & Bustamante, J 2018, ' Inherited p40 ^phox deficiency differs from classic chronic granulomatous disease ', Journal of Clinical Investigation, vol. 128, no. 9, pp. 3957-3975. https://doi.org/10.1172/JCI97116

Inherited p40 ^phox deficiency differs from classic chronic granulomatous disease . / Van De Geer, Annemarie; Nieto-Patlán, Alejandro; Kuhns, Douglas B. et al.

In: Journal of Clinical Investigation, Vol. 128, No. 9, 31.08.2018, p. 3957-3975.

Research output: Contribution to journal › Article › peer-review

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 -

Inherited p40 ^phox deficiency differs from classic chronic granulomatous disease

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