Type I glycogen storage diseases: disorders of the glucose‐6‐phosphatase/glucose‐6‐phosphate transporter complexes

Abstract

Disorders of the glucose-6-phosphatase (G6Pase)/glucose-6-phosphate transporter (G6PT) complexes consist of three subtypes: glycogen storage disease type Ia (GSD-Ia), deficient in the liver/kidney/intestine-restricted G6Pase-α (or G6PC); GSD-Ib, deficient in a ubiquitously expressed G6PT (or SLC37A4); and G6Pase-β deficiency or severe congenital neutropenia syndrome type 4 (SCN4), deficient in the ubiquitously expressed G6Pase-β (or G6PC3). G6Pase-α and G6Pase-β are glucose-6-phosphate (G6P) hydrolases with active sites lying inside the endoplasmic reticulum (ER) lumen and as such are dependent upon the G6PT to translocate G6P from the cytoplasm into the lumen. The tissue expression profiles of the G6Pase enzymes dictate the disease's phenotype. A functional G6Pase-α/G6PT complex maintains interprandial glucose homeostasis, while a functional G6Pase-β/G6PT complex maintains neutrophil/macrophage energy homeostasis and functionality. G6Pase-β deficiency is not a glycogen storage disease but biochemically it is a GSD-I related syndrome (GSD-Irs). GSD-Ia and GSD-Ib patients manifest a common metabolic phenotype of impaired blood glucose homeostasis not shared by GSD-Irs. GSD-Ib and GSD-Irs patients manifest a common myeloid phenotype of neutropenia and neutrophil/macrophage dysfunction not shared by GSD-Ia. While a disruption of the activity of the G6Pase-α/G6PT complex readily explains why GSD-Ia and GSD-Ib patients exhibit impaired glucose homeostasis, the basis for neutropenia and myeloid dysfunction in GSD-Ib and GSD-Irs are only now starting to be understood. Animal models of all three disorders are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches, including gene therapy.

Recent development and gene therapy for glycogen storage disease type Ia

“…1–3 The incidence of GSD-I is approximately 1 in 100,000, with GSD-Ia being the most prevalent form, representing approximately 80% of cases. G6Pase-α catalyzes the hydrolysis of G6P to glucose and phosphate in the terminal steps of gluconeogenesis and glycogenolysis, and is primarily expressed in the liver, kidney, and intestine.…”

“…G6Pase-α catalyzes the hydrolysis of G6P to glucose and phosphate in the terminal steps of gluconeogenesis and glycogenolysis, and is primarily expressed in the liver, kidney, and intestine. 1–3 The active site of G6Pase-α lies on the luminal side of the endoplasmic reticulum (ER), inaccessible to the cytoplasm. 4 Therefore, for G6P hydrolysis to occur in vivo , the G6P substrate must be translocated from the cytoplasm into the ER lumen by the G6PT.…”

“…4 Therefore, for G6P hydrolysis to occur in vivo , the G6P substrate must be translocated from the cytoplasm into the ER lumen by the G6PT. 1–3 Accordingly, G6P transport and hydrolysis are tightly coupled events and the primary function of the G6Pase-α/G6PT complex is to maintain interprandial blood glucose homeostasis. 1–3 Patients affected by GSD-Ia are unable to maintain glucose homeostasis and present with fasting hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, and growth retardation.…”

Novel SLC37A4 Mutations in Korean Patients With Glycogen Storage Disease Ib

“…The disease has an overall incidence of approximately 1 in 100,000 individuals [12]. In this complex, G6Pase-α and G6PT are functionally coupled; G6PT transports G6P from the cytoplasm into the lumen of the endoplasmic reticulum, where it is hydrolyzed to glucose and inorganic phosphate by G6Pase-α [3].…”

“…A functional G6Pase-α/G6PT complex maintains interprandial glucose homeostasis. Specifically, the complex serves as a catalyst in the hydrolysis of intracellular G6P to glucose in the terminal step of gluconeogenesis and glycogenolysis in the liver, kidney, and intestine [23]. Mutations in the G6PC gene, which encodes G6Pase-α, are responsible for approximately 80% of all GSD I cases, classified as GSD Ia.…”