Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

Abstract

Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6-phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.

Figure 1

The primary anabolic and catabolic pathways of glucose-6-phosphate in gluconeogenic organs. G6Pase-α and G6PT are shown embedded within the membrane of the endoplasmic reticulum. GLUT2, the transporter responsible for the transport of glucose in and out of the cell in liver, kidney and intestine, is shown embedded in the plasma membrane. Abbreviations: G6P, glucose-6-phosphate; G6Pase-α, glucose-6-phosphatase-α; G6PT, glucose-6-phosphate transporter; GLUT2, solute carrier family 2, facilitated glucose transporter member 2; P, phosphate; P_i, inorganic phosphate; UDP, uridine diphosphate.

Figure 2

Glucose homeostasis in gluconeogenic organs and neutrophils. (1) Interprandial glucose homestasis is maintained by the endoplasmic reticulum-associated G6PT/G6Pase-α complex.^, Disruption of G6PT results in glycogen storage disease (GSD) type Ib, whereas disruption of G6Pase-α results in GSD-Ia. G6Pase-α is expressed primarily in the liver, kidney and intestine and hydrolyzes G6P to glucose and phosphate, whereas G6PT is ubiquitously expressed and transports G6P from the cytoplasm into the lumen of the endoplasmic reticulum. Glucose generated in the gluconeogenic organs is released into the blood for use by nongluconeogenic organs between meals. without this pathway, blood glucose homeostasis is lost. (2) Neutrophil homeostasis is maintained by the endoplasmic reticulum-associated G6PT/G6Pase-β complex.^,, Unlike G6Pase-α, G6Pase-β is ubiquitously expressed. The G6PT/G6Pase-β complex acts in a manner similar to the G6PT/G6Pase-α complex, with G6PT transporting G6P from the cytoplasm into the lumen of the endoplasmic reticulum and G6Pase-β hydrolyzing G6P to glucose to maintain energy homeostasis in neutrophils. Deficiencies in G6PT (GSD-Ib) or G6Pase-α (GSD-Ia) result in a disturbed blood glucose homeostasis. Deficiencies in G6PT (GSD-Ib) or G6Pase-β result in neutrophil dysfunction. The common role of G6PT explains the neutrophil dysfunction seen in GSD-Ib but not GSD-Ia. Abbreviations: G6P, glucose-6-phosphate; G6Pase-α, glucose-6-phosphatase-α; G6Pase-β, glucose-6-phosphatase-β; G6PT, glucose-6-phosphate transporter.

Figure 3

Proposed roles of the active-site residues in G6Pase-α and G6Pase-β during catalysis. To hydrolyze G6P, His176 of G6Pase-α acts as a nucleophile on the phosphate bound by glucose to form a phosphohistidine-enzyme intermediate that is stabilized by hydrogen bonds with Arg83. His119 provides the proton that liberates the glucose molecule. The single thick line represents the general backbone of the protein, which lies within the membrane of the endoplasmic reticulum. The active-site residues in G6Pase-α are Arg83, His119 and His176 and in G6Pase-β are Arg79, His114, and His167 (in parenthesis). Abbreviation: G6Pase, glucose-6-phosphatase.

Figure 4

Proposed pathways for glucose-6-phosphate metabolism in neutrophils. Glucose transported into the cytoplasm via GLUT1, the main glucose transporter in neutrophils, is metabolized by hexokinase to G6P, which can participate in glycolysis, hexose monophosphate shunt or glycogen synthesis or can be transported into the lumen of the endoplasmic reticulum by G6PT. In wild-type neutrophils, G6P localized within the lumen of the endoplasmic reticulum can be hydrolyzed by G6Pase-β, and the resulting glucose is transported back into the cytoplasm to re-enter any of the previously mentioned cytoplasmic pathways. (1) In G6PT-deficient neutrophils, cytoplasmic G6P cannot be transported into the lumen of the endoplasmic reticulum and blocks glucose/G6P recycling. (2) In G6Pase-β-deficient neutrophils, endoplasmic reticulum-localized G6P cannot be hydrolyzed to glucose, thus also blocks glucose/G6P recycling. The GLUT1 transporter, responsible for the transport of glucose in and out of the cell, is shown embedded in the plasma membrane. The G6PT transporter, responsible for the transport of G6P into the endoplasmic reticulum and G6Pase-β, responsible for hydrolyzing G6P to glucose and phosphate, are shown embedded in the endoplasmic reticulum membrane with 10 and nine transmembrane helices, respectively. Abbreviations: G6P, glucose-6-phosphate; G6Pase-β, glucose-6-phosphatase-β; G6PT, glucose-6-phosphate transporter, GLUT1, solute carrier family 2, facilitated glucose transporter member 1; HMS, hexose monophosphate shunt.