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Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications

G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phen...

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Autores principales: Mistry, Anoop, Scambler, Thomas, Parry, David, Wood, Mark, Barcenas-Morales, Gabriela, Carter, Clive, Doffinger, Rainer, Savic, Sinisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681747/
https://www.ncbi.nlm.nih.gov/pubmed/29163546
http://dx.doi.org/10.3389/fimmu.2017.01485
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author Mistry, Anoop
Scambler, Thomas
Parry, David
Wood, Mark
Barcenas-Morales, Gabriela
Carter, Clive
Doffinger, Rainer
Savic, Sinisa
author_facet Mistry, Anoop
Scambler, Thomas
Parry, David
Wood, Mark
Barcenas-Morales, Gabriela
Carter, Clive
Doffinger, Rainer
Savic, Sinisa
author_sort Mistry, Anoop
collection PubMed
description G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.
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spelling pubmed-56817472017-11-21 Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications Mistry, Anoop Scambler, Thomas Parry, David Wood, Mark Barcenas-Morales, Gabriela Carter, Clive Doffinger, Rainer Savic, Sinisa Front Immunol Immunology G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses. Frontiers Media S.A. 2017-11-06 /pmc/articles/PMC5681747/ /pubmed/29163546 http://dx.doi.org/10.3389/fimmu.2017.01485 Text en Copyright © 2017 Mistry, Scambler, Parry, Wood, Barcenas-Morales, Carter, Doffinger and Savic. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Mistry, Anoop
Scambler, Thomas
Parry, David
Wood, Mark
Barcenas-Morales, Gabriela
Carter, Clive
Doffinger, Rainer
Savic, Sinisa
Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications
title Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications
title_full Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications
title_fullStr Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications
title_full_unstemmed Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications
title_short Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications
title_sort glucose-6-phosphatase catalytic subunit 3 (g6pc3) deficiency associated with autoinflammatory complications
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681747/
https://www.ncbi.nlm.nih.gov/pubmed/29163546
http://dx.doi.org/10.3389/fimmu.2017.01485
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