{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:52:50Z","timestamp":1791363170531,"version":"4.3.1"},"reference-count":38,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Severe congenital neutropenia type 4 (SCN-4) is an autosomal recessive condition in which mutations in the G6PC3 gene encoding for the catalytic 3 subunit of glucose-6-phosphatase-\u03b2 result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by compound heterozygous mutations in G6PC3, a previously identified missense mutation in exon 6 (c.758G&amp;gt;A[p.R235H]), and a novel missense mutation in exon 2 (c.325G&amp;gt;A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony\u2013stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient\u2019s neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria\/neutrophil ratios &amp;gt;1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was &amp;lt;25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope\u2013labeled tracers (U-13C-glucose, 13C,15N-glutamine, and U-13C-fructose) demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool, which could explain the dramatic cell dysfunction displayed by the patient\u2019s neutrophils. Preliminary experiments with fructose supplementation to bypass the enzyme block demonstrated that the metabolic profile could be reversed, but was not sustained long enough for functional improvement. In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002225","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T20:49:34Z","timestamp":1607028574000},"page":"5888-5901","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":22,"title":["Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects"],"prefix":"10.1182","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-435X","authenticated-orcid":false,"given":"Christopher","family":"McKinney","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO;"},{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ellison","sequence":"additional","affiliation":[{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie J.","family":"Briones","sequence":"additional","affiliation":[{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5147-073X","authenticated-orcid":false,"given":"Angelina","family":"Baroffio","sequence":"additional","affiliation":[{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9360-4481","authenticated-orcid":false,"given":"John","family":"Murphy","sequence":"additional","affiliation":[{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7368-7611","authenticated-orcid":false,"given":"Alexander D.","family":"Tran","sequence":"additional","affiliation":[{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7296-4963","authenticated-orcid":false,"given":"Julie A.","family":"Reisz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-6490","authenticated-orcid":false,"given":"Angelo","family":"D\u2019Alessandro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4082-7913","authenticated-orcid":false,"given":"Daniel R.","family":"Ambruso","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO;"},{"name":"Center for Cancer and Blood Disorders, Children\u2019s Hospital Colorado, Aurora, CO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"issue":"1","key":"2020120315414261000_B1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1056\/NEJMoa0805051","article-title":"A syndrome with congenital neutropenia and mutations in G6PC3","volume":"360","author":"Boztug","year":"2009","journal-title":"N Engl J Med"},{"issue":"1","key":"2020120315414261000_B2","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s13023-014-0183-8","article-title":"Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French Severe Congenital Neutropenia Registry","volume":"9","author":"Desplantes","year":"2014","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"2020120315414261000_B3","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1750-1172-8-84","article-title":"A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations","volume":"8","author":"Banka","year":"2013","journal-title":"Orphanet J Rare Dis"},{"issue":"3","key":"2020120315414261000_B4","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1172\/JCI30443","article-title":"Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta","volume":"117","author":"Cheung","year":"2007","journal-title":"J Clin Invest"},{"issue":"15","key":"2020120315414261000_B5","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1182\/blood-2009-12-258491","article-title":"Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-beta-deficient neutrophils in a congenital neutropenia syndrome","volume":"116","author":"Jun","year":"2010","journal-title":"Blood"},{"issue":"14","key":"2020120315414261000_B6","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1182\/blood-2010-08-302059","article-title":"G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis","volume":"117","author":"Jun","year":"2011","journal-title":"Blood"},{"issue":"8","key":"2020120315414261000_B7","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/cdd.2013.39","article-title":"Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-\u03b2 (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation","volume":"20","author":"Gautam","year":"2013","journal-title":"Cell Death Differ"},{"issue":"15","key":"2020120315414261000_B8","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1182\/blood-2010-01-265942","article-title":"Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis","volume":"116","author":"McDermott","year":"2010","journal-title":"Blood"},{"issue":"1","key":"2020120315414261000_B9","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1067\/mpd.2001.114718","article-title":"Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease","volume":"139","author":"Kurkchubasche","year":"2001","journal-title":"J Pediatr"},{"issue":"1","key":"2020120315414261000_B10","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/BF00915283","article-title":"Defective bactericidal activity and absence of specific granules in neutrophils from a patient with recurrent bacterial infections","volume":"4","author":"Ambruso","year":"1984","journal-title":"J Clin Immunol"},{"issue":"11","key":"2020120315414261000_B11","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1182\/blood.V92.11.4366","article-title":"In vivo treatment with granulocyte colony-stimulating factor results in divergent effects on neutrophil functions measured in vitro","volume":"92","author":"Leavey","year":"1998","journal-title":"Blood"},{"issue":"6","key":"2020120315414261000_B12","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.4049\/jimmunol.115.6.1650","article-title":"Chemotaxis under agarose: a new and simple method for measuring chemotaxis and spontaneous migration of human polymorphonuclear leukocytes and monocytes","volume":"115","author":"Nelson","year":"1975","journal-title":"J Immunol"},{"issue":"170","key":"2020120315414261000_B13","doi-asserted-by":"crossref","first-page":"PL5","DOI":"10.1126\/stke.2003.170.pl5","article-title":"Measuring chemotaxis and chemokinesis: the under-agarose cell migration assay","volume":"2003","author":"Heit","year":"2003","journal-title":"Sci STKE"},{"issue":"12","key":"2020120315414261000_B14","doi-asserted-by":"crossref","first-page":"5021","DOI":"10.1182\/blood-2002-10-3128","article-title":"Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b)","volume":"101","author":"Kuijpers","year":"2003","journal-title":"Blood"},{"issue":"6","key":"2020120315414261000_B15","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1002\/eji.201142157","article-title":"Phox activity of differentiated PLB-985 cells is enhanced, in an agonist specific manner, by the PLA2 activity of Prdx6-PLA2","volume":"42","author":"Ellison","year":"2012","journal-title":"Eur J Immunol"},{"issue":"2","key":"2020120315414261000_B16","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.bbamcr.2011.11.014","article-title":"Peroxiredoxin 6 translocates to the plasma membrane during neutrophil activation and is required for optimal NADPH oxidase activity","volume":"1823","author":"Ambruso","year":"2012","journal-title":"Biochim Biophys Acta"},{"issue":"8","key":"2020120315414261000_B17","doi-asserted-by":"crossref","first-page":"e0136766","DOI":"10.1371\/journal.pone.0136766","article-title":"INF-\u03b3 Enhances Nox2 Activity by Upregulating phox Proteins When Applied to Differentiating PLB-985 Cells but Does Not Induce Nox2 Activity by Itself","volume":"10","author":"Ellison","year":"2015","journal-title":"PLoS One"},{"issue":"9","key":"2020120315414261000_B18","doi-asserted-by":"crossref","first-page":"4654","DOI":"10.1073\/pnas.080074897","article-title":"Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation","volume":"97","author":"Ambruso","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"issue":"8","key":"2020120315414261000_B19","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/rcm.7834","article-title":"A three-minute method for high-throughput quantitative metabolomics and quantitative tracing experiments of central carbon and nitrogen pathways","volume":"31","author":"Nemkov","year":"2017","journal-title":"Rapid Commun Mass Spectrom"},{"issue":"2","key":"2020120315414261000_B20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/trf.13892","article-title":"Citrate metabolism in red blood cells stored in additive solution-3","volume":"57","author":"D\u2019Alessandro","year":"2017","journal-title":"Transfusion"},{"issue":"4","key":"2020120315414261000_B21","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat Methods"},{"issue":"7","key":"2020120315414261000_B22","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1093\/glycob\/cwr023","article-title":"G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction","volume":"21","author":"Hayee","year":"2011","journal-title":"Glycobiology"},{"issue":"3","key":"2020120315414261000_B23","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.cmet.2017.08.012","article-title":"Cell-Intrinsic Glycogen Metabolism Supports Early Glycolytic Reprogramming Required for Dendritic Cell Immune Responses [published correction appears in Cell Metab. 2019;30(1):225]","volume":"26","author":"Thwe","year":"2017","journal-title":"Cell Metab"},{"issue":"4","key":"2020120315414261000_B24","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1073\/pnas.1816143116","article-title":"Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency","volume":"116","author":"Veiga-da-Cunha","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"2020120315414261000_B25","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1677\/jme.0.0290205","article-title":"Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein","volume":"29","author":"Martin","year":"2002","journal-title":"J Mol Endocrinol"},{"issue":"1-3","key":"2020120315414261000_B26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0014-5793(03)00903-7","article-title":"Identification and characterisation of a new human glucose-6-phosphatase isoform","volume":"551","author":"Guionie","year":"2003","journal-title":"FEBS Lett"},{"issue":"17","key":"2020120315414261000_B27","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1182\/blood-2011-09-377820","article-title":"Glucose-6-phosphatase-\u03b2, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality","volume":"119","author":"Jun","year":"2012","journal-title":"Blood"},{"issue":"7","key":"2020120315414261000_B28","doi-asserted-by":"crossref","first-page":"5194","DOI":"10.1074\/jbc.M306973200","article-title":"Mechanism of actin polymerization in cellular ATP depletion","volume":"279","author":"Atkinson","year":"2004","journal-title":"J Biol Chem"},{"issue":"4","key":"2020120315414261000_B29","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1161\/ATVBAHA.111.226845","article-title":"Regulation of neutrophil function by adenosine","volume":"32","author":"Barletta","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"3","key":"2020120315414261000_B30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1089\/ars.2017.7014","article-title":"Extraction and Quantitation of Nicotinamide Adenine Dinucleotide Redox Cofactors","volume":"28","author":"Lu","year":"2018","journal-title":"Antioxid Redox Signal"},{"key":"2020120315414261000_B31","volume-title":"Molecular Cell Biology","author":"Lodish","year":"2000","edition":"4th ed."},{"issue":"4","key":"2020120315414261000_B32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1042\/cs1030403","article-title":"Glutamine plays a role in superoxide production and the expression of p47phox, p22phox and gp91phox in rat neutrophils","volume":"103","author":"Pithon-Curi","year":"2002","journal-title":"Clin Sci (Lond)"},{"issue":"12","key":"2020120315414261000_B33","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1182\/blood-2005-11-4370","article-title":"The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy","volume":"107","author":"Rosenberg","year":"2006","journal-title":"Blood"},{"issue":"7433","key":"2020120315414261000_B34","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature11743","article-title":"Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells","volume":"493","author":"Maddocks","year":"2013","journal-title":"Nature"},{"issue":"2","key":"2020120315414261000_B35","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.molcel.2014.07.001","article-title":"Localization of NADPH production: a wheel within a wheel [published correction appears in Mol Cell. 2014;56(4):608]","volume":"55","author":"Maddocks","year":"2014","journal-title":"Mol Cell"},{"issue":"8","key":"2020120315414261000_B36","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1016\/j.tiv.2015.08.013","article-title":"In vitro fructose exposure overactivates NADPH oxidase and causes oxidative stress in the isolated rat aorta","volume":"29","author":"Almenara","year":"2015","journal-title":"Toxicol In Vitro"},{"issue":"8","key":"2020120315414261000_B37","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1093\/ajh\/hpu021","article-title":"Alterations in neutrophil production and function at an early stage in the high-fructose rat model of metabolic syndrome","volume":"27","author":"Tagzirt","year":"2014","journal-title":"Am J Hypertens"},{"issue":"1","key":"2020120315414261000_B38","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/jimd.12187","article-title":"Inborn errors of metabolite repair","volume":"43","author":"Veiga-da-Cunha","year":"2020","journal-title":"J Inherit Metab Dis"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/4\/23\/5888\/1791861\/advancesadv2020002225.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/4\/23\/5888\/1791861\/advancesadv2020002225.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T15:02:19Z","timestamp":1697295739000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/4\/23\/5888\/474276\/Metabolic-abnormalities-in-G6PC3deficient-human"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,1]]},"references-count":38,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2020,12,8]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2020002225","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,1]]}}}