Submitted December 18, 2007
Accepted April 1, 2008
Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib
So Youn Kim, Hyun Sik Jun, Paul A. Mead, Brian C. Mansfield, and Janice Y. Chou*
Section on Cellular Differentiation, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: chouja{at}mail.nih.gov.
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that works with a liver/kidney/intestine-restricted glucose-6-phosphatase-alpha (G6Pase-alpha) to maintain glucose homeostasis between meals. Clinically, GSD-Ib patients manifest disturbed glucose homeostasis and neutrophil dysfunctions but the cause of the latter is unclear. Neutrophils express the ubiquitously expressed G6PT and G6Pase-beta that together transport G6P into the endoplasmic reticulum (ER) lumen and hydrolyze it to glucose. Since G6PT-deficient neutrophils are expected to be unable to produce endogenous glucose, we hypothesized this would lead to ER stress and increased apoptosis. Using GSD-Ib mice, we show that GSD-Ib neutrophils exhibit increases in the production of ER chaperons and oxidative stress, consistent with ER stress, and increased Annexin V binding and caspase-3 activation, consistent with an increased rate of apoptosis. Bax activation, mitochondrial release of pro-apoptotic effectors, and caspase-9 activation demonstrate the involvement of the intrinsic mitochondrial pathway in these processes. The results demonstrate that G6P translocation and hydrolysis are required for normal neutrophil functions and support the hypothesis that neutrophil dysfunction in GSD-Ib is due, at least in part, to ER stress and increased apoptosis.
