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Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis

  1. Author:
    McDermott, D. H.
    De Ravin, S. S.
    Jun, H. S.
    Liu, Q. A.
    Priel, D. A. L.
    Noel, P.
    Takemoto, C. M.
    Ojode, T.
    Paul, S. M.
    Dunsmore, K. P.
    Hilligoss, D.
    Marquesen, M.
    Ulrick, J.
    Kuhns, D. B.
    Chou, J. Y.
    Malech, H. L.
    Murphy, P. M.

  2. Author Address

    [McDermott, David H.; Liu, Qian; Ojode, Teresa; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [De Ravin, Suk See; Hilligoss, Dianne; Marquesen, Martha; Ulrick, Jean; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Jun, Hyun Sik; Chou, Janice Y.] NICHHD, Sect Cellular Differentiat, NIH, Bethesda, MD 20892 USA. [Priel, Debra A. Long; Kuhns, Douglas B.] NCI, Clin Serv Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Noel, Pierre] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Takemoto, Clifford M.] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Baltimore, MD USA. [Paul, Scott M.] NIH, Dept Phys Med & Rehabil, Ctr Clin, Bethesda, MD 20892 USA. [Dunsmore, Kimberly P.] Univ Virginia, Hlth Sci Ctr, Div Hematol Oncol, Dept Pediat, Charlottesville, VA USA.;McDermott, DH, NIAID, Lab Mol Immunol, NIH, Bldg 10,Rm 11N107, Bethesda, MD 20892 USA.;dmcdermott@niaid.nih.gov
    1. Year: 2010
    2. Date: Oct
  2. Journal: Blood
    1. 116
    2. 15
    3. Pages: 2793-2802
  4. Type of Article: Article
  5. ISSN: 0006-4971
  1. Abstract:

    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. (Blood.2010;116(15):2793-2802)

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External Sources

  1. View Full Text
  2. DOI: 10.1182/blood-2010-01-265942
  3. View record in Web of Science®
  4. WOS: 000282956700028

Library Notes

  1. Fiscal Year: FY2010-2011
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