Human Molecular Genetics Advance Access published online on August 12, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg263
© 2003 by Oxford University Press
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1 Section on Cellular Differentiation, Heritable Disorders Branch, National Institutes of Health, Bethesda, MD 20892
* To whom correspondence should be addressed. E-mail: chou{at}helix.nih.gov.
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis, and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.
Article
Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter
2 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
3 Department of Pediatrics, University of Southern California School of Medicine, Los Angeles, CA 90027
4 Pediatric Division, Ben-Gurion University of the Negev, Beer-Sheva, Israel
5 Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702
6 Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
7 Section on Cellular Differentiation, Heritable Disorders Branch, National Institutes of Health, Building 10, Room 9S241, Bethesda, MD 20892-1830
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