Journal
BLOOD
Volume 123, Issue 18, Pages 2843-2853Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-05-502435
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Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
- University of Florida Foundation
- Rural Development Administration, Republic of Korea [PJ008196/PJ008127]
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Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive syndrome characterized by neutropenia and impaired glucose homeostasis resulting from a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT). The underlying cause of GSD-Ib neutropenia is an enhanced neutrophil apoptosis, but patients also manifest neutrophil dysfunction of unknown etiology. Previously, we showed G6PT interacts with the enzyme glucose-6-phosphatase-beta (G6Pase-beta) to regulate the availability of G6P/glucose in neutrophils. Adeficiency in G6Pase-beta activity in neutrophils impairs both their energy homeostasis and function. We now show that G6PT-deficient neutrophils from GSD-Ib patients are similarly impaired. Their energy impairment is characterized by decreased glucose uptake and reduced levels of intracellular G6P, lactate, adenosine triphosphate, and reduced NAD phosphate, whereas functional impairment is reflected in reduced neutrophil respiratory burst, chemotaxis, and calcium mobilization. We further show that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the hypoxia-inducible factor-1 alpha/peroxisome-proliferators-activated receptor-gamma pathway.
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