title: Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib.
abstract: 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-β (G6Pase-β) to regulate the availability of G6P/glucose in neutrophils. A deficiency in G6Pase-β 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-1α/peroxisome-proliferators-activated receptor-γ pathway.
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD;
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.forename: David A
authors.initials: DA
authors.lastname: Weinstein
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Lee
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017920:Antiporters / Q000172:deficiency / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016130:Immunophenotyping; D042541:Intracellular Space / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D017920:Antiporters; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D047495:PPAR gamma; C111261:glucose 6-phosphate(transporter); D019344:Lactic Acid; D009249:NADP; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; D005952:Glucose-6-Phosphatase; D005947:Glucose