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Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency.

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Veiga da Cunha, Maria [UCL] Chevalier, Nathalie [UCL] Stephenne, Xavier [UCL] Defour, Jean-Philippe [UCL] Paczia, Nicole Achouri, Younes [UCL] Dewulf, Joseph P. [UCL] Bommer, Guido [UCL] Van Schaftingen, Emile [UCL]

Neutropenia represents an important problem in patients with genetic deficiency in either the glucose-6-phosphate transporter of the endoplasmic reticulum (G6PT/SLC37A4) or G6PC3, an endoplasmic reticulum phosphatase homologous to glucose-6-phosphatase. While affected granulocytes show reduced glucose utilization, the underlying mechanism is unknown and causal therapies are lacking. Using a combination of enzymological, cell-culture, and in vivo approaches, we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low- hexokinases, which catalyze the first step in glycolysis in most tissues. We show that 1,5AG6P is made by phosphorylation of 1,5-anhydroglucitol, a compound normally present in human plasma, by side activities of ADP-glucokinase and low- hexokinases. Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (∼3 mM) that strongly inhibit hexokinase activity. In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death. Treating G6PC3-deficient mice with an inhibitor of the kidney glucose transporter SGLT2 to lower their blood level of 1,5-anhydroglucitol restored a normal neutrophil count, while administration of 1,5-anhydroglucitol had the opposite effect. In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2019
Language Anglais
Journal information "Proceedings of the National Academy of Sciences of the United States of America" - Vol. 116, no. 4, p. 1241-1250 (2019)
Peer reviewed yes
Publisher National Academy of Sciences ((United States) Washington, DC)
issn 0027-8424
e-issn 1091-6490
Publication status Publié
Affiliations UCL - SSS/DDUV - Institut de Duve
UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique
UCL - SSS/DDUV/LPAD - Liver and pancreas differentiation
UCL - SSS/DDUV/SIGN - Cell signalling
UCL - SSS/IREC/PEDI - Pôle de Pédiatrie
UCL - (SLuc) Service de biochimie médicale
UCL - (SLuc) Service de biologie hématologique
UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique
Keywords SLGT2 inhibitors ; 1;5-anhydroglucitol ; Glucose-6-phosphatase-β ; Metabolite repair ; Neutropenia
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Bibliographic reference Veiga da Cunha, Maria ; Chevalier, Nathalie ; Stephenne, Xavier ; Defour, Jean-Philippe ; Paczia, Nicole ; et. al. Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency.. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, no. 4, p. 1241-1250 (2019)
Permanent URL http://hdl.handle.net/2078.1/211478