G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction
Open Access
- 8 March 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Glycobiology
- Vol. 21 (7), 914-924
- https://doi.org/10.1093/glycob/cwr023
Abstract
Glucose-6-phosphatase, an enzyme localized in the endoplasmic reticulum (ER), catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate. In humans, there are three differentially expressed glucose-6-phosphatase catabolic genes (G6PC1–3). Recently, it has been shown that mutations in the G6PC3 gene result in a syndrome associating congenital neutropenia and various organ malformations. The enzymatic function of G6PC3 is dependent on G6P transport into the ER, mediated by G6P translocase (G6PT). Mutations in the gene encoding G6PT result in glycogen storage disease type-1b (GSD-1b). Interestingly, GSD-1b patients exhibit a similar neutrophil dysfunction to that observed in G6PC3-deficient patients. To better understand the causes of neutrophil dysfunction in both diseases, we have studied the neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of patients with G6PC3 and G6PT syndromes. Unexpectedly, sodium dodecyl sulfate–polyacrylamide gel electrophoresis experiments indicated hypo-glycosylation of gp91phox, the electron-transporting component of the NADPH oxidase, in all of these patients. Rigorous mass spectrometric glycomic profiling showed that most of the complex-type antennae which characterize the neutrophil N-glycome of healthy individuals were severely truncated in the patients' neutrophils. A comparable truncation of the core 2 antenna of the O-glycans was also observed. This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation.Keywords
This publication has 60 references indexed in Scilit:
- Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexisBlood, 2010
- Impaired macrophage function following bacterial stimulation in chronic granulomatous diseaseImmunology, 2009
- Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's diseaseThe Journal of Experimental Medicine, 2009
- A Syndrome with Congenital Neutropenia and Mutations inG6PC3New England Journal of Medicine, 2009
- Structural characterisation of neutrophil glycans by ultra sensitive mass spectrometric glycomics methodologyGlycoconjugate Journal, 2008
- Maintenance of luminal NADPH in the endoplasmic reticulum promotes the survival of human neutrophil granulocytesFEBS Letters, 2008
- Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase–βJCI Insight, 2007
- Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literatureEuropean Journal of Pediatrics, 2005
- Neutrophil metabolic dysfunction in genetically heterogeneous patients with glycogen storage disease type 1bJournal of Inherited Metabolic Disease, 1986
- Human erythrocyte membrane glycoprotein: A re-evaluation of the molecular weight as determined by SDS polyacrylamide gel electrophoresisBiochemical and Biophysical Research Communications, 1971