Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects
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-β result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by co...
Gespeichert in:
| Veröffentlicht in: | Blood advances 2020-12, Vol.4 (23), p.5888-5901 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 5901 |
|---|---|
| container_issue | 23 |
| container_start_page | 5888 |
| container_title | Blood advances |
| container_volume | 4 |
| creator | McKinney, Christopher Ellison, Michael Briones, Natalie J. Baroffio, Angelina Murphy, John Tran, Alexander D. Reisz, Julie A. D'Alessandro, Angelo Ambruso, Daniel R. |
| description | 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-β 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>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient's neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was |
| doi_str_mv | 10.1182/bloodadvances.2020002225 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7724913</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S2473952920320140</els_id><sourcerecordid>2466292462</sourcerecordid><originalsourceid>FETCH-LOGICAL-c534t-5406b1657bd1a75a3bfc7349121b228dd6297bc556f2314bf9e429434b3512863</originalsourceid><addsrcrecordid>eNqFUU1vFCEYJkZjm9q_YOboZerwAsNyMdGNVpMaPegZgXnHxTCwArOJ_142W1d78gIkPF95HkI6OtxQuoGXNqQ0melgosNyAwMMwwAA4hG5BC5ZrwSTj89vUBfkupQfDUTlyISCp-SCMRBKKHVJvn3EamwK3nXGxpQXE3z1WDofu9vx85b1E87eeYy1262LiV3Etea03_lQuoxlDfWILXjAjN28Rld9iiZ0jYeulmfkyWxCwev7-4p8fff2y_Z9f_fp9sP29V3vBOO1F3wYLR2FtBM1UhhmZycZVxSoBdhM0whKWifEOAOj3M4KOSjOuGWCwmZkV-TVSXe_2gUn1wJnE_Q--8XkXzoZrx_-RL_T39NBSwnNhjWBF_cCOf1csVS9-OIwBBMxrUUDH1uGdkKDbk5Ql1MpGeezDR30cSP9YCP9d6NGff5vzDPxzyIN8OYEwFbWwWPW5di-w8nn1qeekv-_y2-O-Klt</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2466292462</pqid></control><display><type>article</type><title>Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>McKinney, Christopher ; Ellison, Michael ; Briones, Natalie J. ; Baroffio, Angelina ; Murphy, John ; Tran, Alexander D. ; Reisz, Julie A. ; D'Alessandro, Angelo ; Ambruso, Daniel R.</creator><creatorcontrib>McKinney, Christopher ; Ellison, Michael ; Briones, Natalie J. ; Baroffio, Angelina ; Murphy, John ; Tran, Alexander D. ; Reisz, Julie A. ; D'Alessandro, Angelo ; Ambruso, Daniel R.</creatorcontrib><description>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-β 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>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient's neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled 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's 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.
•G6PC3 deficiency results in neutrophil chemotactic and killing defects due to impaired actin assembly, CD11b expression, and O2− production.•Metabolomic flux experiments demonstrate derangements in glycolysis, hexose monophosphate shunt, glutaminolysis, and redox pathways.
[Display omitted]</description><identifier>ISSN: 2473-9529</identifier><identifier>EISSN: 2473-9537</identifier><identifier>DOI: 10.1182/bloodadvances.2020002225</identifier><identifier>PMID: 33259599</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Child ; Congenital Bone Marrow Failure Syndromes ; Glucose-6-Phosphatase ; Granulocyte Colony-Stimulating Factor ; Humans ; Neutropenia - genetics ; Neutrophils ; Phagocytes, Granulocytes, and Myelopoiesis</subject><ispartof>Blood advances, 2020-12, Vol.4 (23), p.5888-5901</ispartof><rights>2020 American Society of Hematology</rights><rights>2020 by The American Society of Hematology.</rights><rights>2020 by The American Society of Hematology 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c534t-5406b1657bd1a75a3bfc7349121b228dd6297bc556f2314bf9e429434b3512863</citedby><cites>FETCH-LOGICAL-c534t-5406b1657bd1a75a3bfc7349121b228dd6297bc556f2314bf9e429434b3512863</cites><orcidid>0000-0002-7296-4963 ; 0000-0002-9360-4481 ; 0000-0002-2258-6490 ; 0000-0002-8139-435X ; 0000-0002-4082-7913 ; 0000-0001-5147-073X ; 0000-0002-7368-7611</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724913/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724913/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33259599$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McKinney, Christopher</creatorcontrib><creatorcontrib>Ellison, Michael</creatorcontrib><creatorcontrib>Briones, Natalie J.</creatorcontrib><creatorcontrib>Baroffio, Angelina</creatorcontrib><creatorcontrib>Murphy, John</creatorcontrib><creatorcontrib>Tran, Alexander D.</creatorcontrib><creatorcontrib>Reisz, Julie A.</creatorcontrib><creatorcontrib>D'Alessandro, Angelo</creatorcontrib><creatorcontrib>Ambruso, Daniel R.</creatorcontrib><title>Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects</title><title>Blood advances</title><addtitle>Blood Adv</addtitle><description>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-β 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>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient's neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled 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's 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.
•G6PC3 deficiency results in neutrophil chemotactic and killing defects due to impaired actin assembly, CD11b expression, and O2− production.•Metabolomic flux experiments demonstrate derangements in glycolysis, hexose monophosphate shunt, glutaminolysis, and redox pathways.
[Display omitted]</description><subject>Child</subject><subject>Congenital Bone Marrow Failure Syndromes</subject><subject>Glucose-6-Phosphatase</subject><subject>Granulocyte Colony-Stimulating Factor</subject><subject>Humans</subject><subject>Neutropenia - genetics</subject><subject>Neutrophils</subject><subject>Phagocytes, Granulocytes, and Myelopoiesis</subject><issn>2473-9529</issn><issn>2473-9537</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1vFCEYJkZjm9q_YOboZerwAsNyMdGNVpMaPegZgXnHxTCwArOJ_142W1d78gIkPF95HkI6OtxQuoGXNqQ0melgosNyAwMMwwAA4hG5BC5ZrwSTj89vUBfkupQfDUTlyISCp-SCMRBKKHVJvn3EamwK3nXGxpQXE3z1WDofu9vx85b1E87eeYy1262LiV3Etea03_lQuoxlDfWILXjAjN28Rld9iiZ0jYeulmfkyWxCwev7-4p8fff2y_Z9f_fp9sP29V3vBOO1F3wYLR2FtBM1UhhmZycZVxSoBdhM0whKWifEOAOj3M4KOSjOuGWCwmZkV-TVSXe_2gUn1wJnE_Q--8XkXzoZrx_-RL_T39NBSwnNhjWBF_cCOf1csVS9-OIwBBMxrUUDH1uGdkKDbk5Ql1MpGeezDR30cSP9YCP9d6NGff5vzDPxzyIN8OYEwFbWwWPW5di-w8nn1qeekv-_y2-O-Klt</recordid><startdate>20201208</startdate><enddate>20201208</enddate><creator>McKinney, Christopher</creator><creator>Ellison, Michael</creator><creator>Briones, Natalie J.</creator><creator>Baroffio, Angelina</creator><creator>Murphy, John</creator><creator>Tran, Alexander D.</creator><creator>Reisz, Julie A.</creator><creator>D'Alessandro, Angelo</creator><creator>Ambruso, Daniel R.</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7296-4963</orcidid><orcidid>https://orcid.org/0000-0002-9360-4481</orcidid><orcidid>https://orcid.org/0000-0002-2258-6490</orcidid><orcidid>https://orcid.org/0000-0002-8139-435X</orcidid><orcidid>https://orcid.org/0000-0002-4082-7913</orcidid><orcidid>https://orcid.org/0000-0001-5147-073X</orcidid><orcidid>https://orcid.org/0000-0002-7368-7611</orcidid></search><sort><creationdate>20201208</creationdate><title>Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects</title><author>McKinney, Christopher ; Ellison, Michael ; Briones, Natalie J. ; Baroffio, Angelina ; Murphy, John ; Tran, Alexander D. ; Reisz, Julie A. ; D'Alessandro, Angelo ; Ambruso, Daniel R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c534t-5406b1657bd1a75a3bfc7349121b228dd6297bc556f2314bf9e429434b3512863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Child</topic><topic>Congenital Bone Marrow Failure Syndromes</topic><topic>Glucose-6-Phosphatase</topic><topic>Granulocyte Colony-Stimulating Factor</topic><topic>Humans</topic><topic>Neutropenia - genetics</topic><topic>Neutrophils</topic><topic>Phagocytes, Granulocytes, and Myelopoiesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McKinney, Christopher</creatorcontrib><creatorcontrib>Ellison, Michael</creatorcontrib><creatorcontrib>Briones, Natalie J.</creatorcontrib><creatorcontrib>Baroffio, Angelina</creatorcontrib><creatorcontrib>Murphy, John</creatorcontrib><creatorcontrib>Tran, Alexander D.</creatorcontrib><creatorcontrib>Reisz, Julie A.</creatorcontrib><creatorcontrib>D'Alessandro, Angelo</creatorcontrib><creatorcontrib>Ambruso, Daniel R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (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>Blood advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McKinney, Christopher</au><au>Ellison, Michael</au><au>Briones, Natalie J.</au><au>Baroffio, Angelina</au><au>Murphy, John</au><au>Tran, Alexander D.</au><au>Reisz, Julie A.</au><au>D'Alessandro, Angelo</au><au>Ambruso, Daniel R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects</atitle><jtitle>Blood advances</jtitle><addtitle>Blood Adv</addtitle><date>2020-12-08</date><risdate>2020</risdate><volume>4</volume><issue>23</issue><spage>5888</spage><epage>5901</epage><pages>5888-5901</pages><issn>2473-9529</issn><eissn>2473-9537</eissn><abstract>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-β 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>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient's neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled 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's 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.
•G6PC3 deficiency results in neutrophil chemotactic and killing defects due to impaired actin assembly, CD11b expression, and O2− production.•Metabolomic flux experiments demonstrate derangements in glycolysis, hexose monophosphate shunt, glutaminolysis, and redox pathways.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33259599</pmid><doi>10.1182/bloodadvances.2020002225</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-7296-4963</orcidid><orcidid>https://orcid.org/0000-0002-9360-4481</orcidid><orcidid>https://orcid.org/0000-0002-2258-6490</orcidid><orcidid>https://orcid.org/0000-0002-8139-435X</orcidid><orcidid>https://orcid.org/0000-0002-4082-7913</orcidid><orcidid>https://orcid.org/0000-0001-5147-073X</orcidid><orcidid>https://orcid.org/0000-0002-7368-7611</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2473-9529 |
| ispartof | Blood advances, 2020-12, Vol.4 (23), p.5888-5901 |
| issn | 2473-9529 2473-9537 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7724913 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Child Congenital Bone Marrow Failure Syndromes Glucose-6-Phosphatase Granulocyte Colony-Stimulating Factor Humans Neutropenia - genetics Neutrophils Phagocytes, Granulocytes, and Myelopoiesis |
| title | Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T21%3A25%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Metabolic%20abnormalities%20in%20G6PC3-deficient%20human%20neutrophils%20result%20in%20severe%20functional%20defects&rft.jtitle=Blood%20advances&rft.au=McKinney,%20Christopher&rft.date=2020-12-08&rft.volume=4&rft.issue=23&rft.spage=5888&rft.epage=5901&rft.pages=5888-5901&rft.issn=2473-9529&rft.eissn=2473-9537&rft_id=info:doi/10.1182/bloodadvances.2020002225&rft_dat=%3Cproquest_pubme%3E2466292462%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2466292462&rft_id=info:pmid/33259599&rft_els_id=S2473952920320140&rfr_iscdi=true |