Document Detail

Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis.
MedLine Citation:
PMID:  20616219     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Intramural     Date:  2010-07-08
Journal Detail:
Title:  Blood     Volume:  116     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-15     Completed Date:  2010-11-05     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2793-802     Citation Subset:  AIM; IM    
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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MeSH Terms
Gene Expression
Glucose-6-Phosphatase / genetics*
Glycogen Storage Disease Type I / genetics*
Mice, Inbred C57BL
Mice, Knockout
Mutation, Missense
Neutropenia / congenital*,  enzymology,  genetics*
Neutrophils / metabolism
Receptors, CXCR4 / genetics*
Reg. No./Substance:
0/CXCR4 protein, human; 0/CXCR4 protein, mouse; 0/Receptors, CXCR4; EC; EC protein, human

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