G6PC3 mutations are associated with a major defect of glycosylation: A novel mechanism for neutrophil dysfunction

Bu'Hussain Hayee, Aristotelis Antonopoulos, Emma J. Murphy, Farooq Z. Rahman, Gavin Sewell, Bradley N. Smith, Sara McCartney, Mark Furman, Georgina Hall, Stuart L. Bloom, Stuart M. Haslam, Howard R. Morris, Kaan Boztug, Christoph Klein, Bryan Winchester, Edgar Pick, David C. Linch, Rosemary E. Gale, Andrew M. Smith, Anne DellAnthony W. Segal

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)914-924
Number of pages11
Issue number7
StatePublished - Jul 2011


FundersFunder number
Wellcome Trust
Biotechnology and Biological Sciences Research CouncilBBF0083091


    • G6PC3
    • glycogen storage disease type-1b
    • glycosylation
    • neutrophil
    • respiratory burst


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