| Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. | |
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MedLine Citation:
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PMID: 20616219 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mutations in more than 15 genes are now known to cause severe congenital neutropenia (SCN); however, the pathologic mechanisms of most genetic defects are not fully defined. Deficiency of G6PC3, a glucose-6-phosphatase, causes a rare multisystem syndrome with SCN first described in 2009. We identified a family with 2 children with homozygous G6PC3 G260R mutations, a loss of enzymatic function, and typical syndrome features with the exception that their bone marrow biopsy pathology revealed abundant neutrophils consistent with myelokathexis. This pathologic finding is a hallmark of another type of SCN, WHIM syndrome, which is caused by gain-of-function mutations in CXCR4, a chemokine receptor and known neutrophil bone marrow retention factor. We found markedly increased CXCR4 expression on neutrophils from both our G6PC3-deficient patients and G6pc3(-/-) mice. In both patients, granulocyte colony-stimulating factor treatment normalized CXCR4 expression and neutrophil counts. In G6pc3(-/-) mice, the specific CXCR4 antagonist AMD3100 rapidly reversed neutropenia. Thus, myelokathexis associated with abnormally high neutrophil CXCR4 expression may contribute to neutropenia in G6PC3 deficiency and responds well to granulocyte colony-stimulating factor. |
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Authors:
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David H McDermott; Suk See De Ravin; Hyun Sik Jun; Qian Liu; Debra A Long Priel; Pierre Noel; Clifford M Takemoto; Teresa Ojode; Scott M Paul; Kimberly P Dunsmore; Dianne Hilligoss; Martha Marquesen; Jean Ulrick; Douglas B Kuhns; Janice Y Chou; Harry L Malech; Philip M Murphy |
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Publication Detail:
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Type: Case Reports; Journal Article; Research Support, N.I.H., Intramural Date: 2010-07-08 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-15 Completed Date: 2010-11-05 Revised Date: 2011-10-14 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 2793-802 Citation Subset: AIM; IM |
Affiliation:
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Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. dmcdermott@niaid.nih.gov |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Animals Child Female Gene Expression Glucose-6-Phosphatase / genetics* Glycogen Storage Disease Type I / genetics* Homozygote Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mutation, Missense Neutropenia / congenital*, enzymology, genetics* Neutrophils / metabolism Receptors, CXCR4 / genetics* Syndrome |
| Chemical | |
Reg. No./Substance:
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0/CXCR4 protein, human; 0/CXCR4 protein, mouse; 0/Receptors, CXCR4; EC 3.1.3.9/Glucose-6-Phosphatase; EC 3.1.3.9./G6PC3 protein, human |
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