Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-β deficiency.

Glucose-6-phosphatase-β (G6Pase-β or G6PC3) deficiency is characterized by neutropenia and dysfunction in both neutrophils and macrophages. G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. To date, 33 separate G6PC3 mutations have been identified in G6Pase-β-deficient patients but only the p.

Bone marrow-derived cells require a functional glucose 6-phosphate transporter for normal myeloid functions.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT). Glc-6-PT activity has been shown to be critical in the liver and kidney where a deficiency disrupts glucose homeostasis. GSD-Ib patients also have defects in the neutrophil respiratory burst, chemotaxis, and calcium flux.

Increased cellular cholesterol efflux in glycogen storage disease type Ia mice: a potential mechanism that protects against premature atherosclerosis.

Glycogen storage disease type Ia (GSD-Ia) patients manifest a pro-atherogenic lipid profile but are not at elevated risk for developing atherosclerosis. Serum phospholipid, which correlates positively with the scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux, and apolipoprotein A-IV and E, acceptors for ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol transport, are increased in GSD-Ia mice. Importantly, sera from GSD-Ia mice are more efficient than sera from control littermates in promoting SR-BI- and ABCA1-mediated cholesterol effluxes.

Effect of fasting on methionine adenosyltransferase expression and the methionine cycle in the mouse liver.

The effect of fasting on mouse liver methionine adenosyltransferase (MAT I/ III) expression and the regulation of methionine metabolism were investigated. The mRNA level, protein level, and activity of MAT I/III were increased by fasting for 10 or 16 h. In spite of the increase of MAT I/III activity, S-adenosylmethionine, the product of methionine due to MAT I/III, decreased.

Brain contains a functional glucose-6-phosphatase complex capable of endogenous glucose production.

Glucose is absolutely essential for the survival and function of the brain. In our current understanding, there is no endogenous glucose production in the brain, and it is totally dependent upon blood glucose. This glucose is generated between meals by the hydrolysis of glucose-6-phosphate (Glc-6-P) in the liver and the kidney.

A potential new role for muscle in blood glucose homeostasis.

The breakdown of tissue glycogen into glucose is critical for blood glucose homeostasis between meals. In the final steps of glycogenolysis, intracellular glucose 6-phosphate (Glc-6-P) is transported into the endoplasmic reticulum where it is hydrolyzed to glucose by glucose-6-phosphatase (Glc-6-Pase). Although the majority of body glycogen is stored in the muscle, the current dogma holds that Glc-6-Pase (now named Glc-6-Pase-alpha) is expressed only in the liver, kidney, and intestine, implying that muscle glycogen cannot contribute to interprandial blood glucose homeostasis.

The islet-specific glucose-6-phosphatase-related protein, implicated in diabetes, is a glycoprotein embedded in the endoplasmic reticulum membrane.

The islet-specific glucose-6-phosphatase-related protein (IGRP) has no known catalytic activity, but is of interest because it is the source of the peptide autoantigen targeted by a prevalent population of pathogenic CD8(+) T cells in non-obese diabetic mice. To better understand the potential roles of this protein in diabetes mellitus, we examine the subcellular localization and membrane topography of human IGRP. We show that IGRP is a glycoprotein, held in the endoplasmic reticulum by nine transmembrane domains, which is degraded in cells predominantly through the proteasome pathway that generates the major histocompatibility complex class I-presented peptides.

Histidine 167 is the phosphate acceptor in glucose-6-phosphatase-beta forming a phosphohistidine enzyme intermediate during catalysis.

The glucose-6-phosphatase (Glc-6-Pase) family comprises two active endoplasmic reticulum (ER)-associated isozymes: the liver/kidney/intestine Glc-6-Pase-alpha and the ubiquitous Glc-6-Pase-beta. Both share similar kinetic properties. Sequence alignments predict the two proteins are structurally similar.

A glucose-6-phosphate hydrolase, widely expressed outside the liver, can explain age-dependent resolution of hypoglycemia in glycogen storage disease type Ia.

A fine control of the blood glucose level is essential to avoid hyper- or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex.

Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib.

The signature motif in human glucose-6-phosphate transporter is essential for microsomal transport of glucose-6-phosphate.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Sequence alignments identify a signature motif shared by G6PT and a family of transporters of phosphorylated metabolites. Two null signature motif mutations have been identified in the G6PT gene of GSD-Ib patients.

Structure-function analysis of the glucose-6-phosphate transporter deficient in glycogen storage disease type Ib.

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), a 10 transmembrane domain endoplasmic reticulum protein. To date, 69 G6PT mutations, including 28 missenses and 2 codon deletions, have been identified in GSD-Ib patients. We previously characterized 15 of the missense and one codon deletion mutations using a pSVL-based expression assay.

Adenovirus-mediated gene therapy in a mouse model of glycogen storage disease type 1a.

Unlabelled: Glycogen storage disease type 1a (GSD-1a), characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and renal dysfunction, is caused by deficiencies in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. Over the last 20 years, dietary therapies have greatly improved the prognosis of GSD-1a patients. However, the underlying pathological process remains uncorrected and the efficacy of dietary treatment is frequently limited by poor compliance.

Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice.

Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility.

The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis.

Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate.

Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex.

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane.

The molecular basis of glycogen storage disease type 1a: structure and function analysis of mutations in glucose-6-phosphatase.

Glycogen storage disease type 1a is caused by a deficiency in glucose-6-phosphatase (G6Pase), a nine-helical endoplasmic reticulum transmembrane protein required for maintenance of glucose homeostasis. To date, 75 G6Pase mutations have been identified, including 48 mutations resulting in single-amino acid substitutions. However, only 19 missense mutations have been functionally characterized.