Glucose 6-phosphatase - Clinical Significance

Clinical Significance

Mutations of the Glucose-6-phosphatase system specifically the Glucose-6-phosphatase-α subunit (G6Pase- α), Glucose-6-transporter (G6PT), and Glucose-6-phosphatase-β (G6Pase- β or G6PC3) subunits lead to deficiencies in the maintenance of interprandial glucose homeostasis and neutrophil function and homeostasis. Mutations in both G6Pase- α and G6PT lead to Glycogen Storage Disease Type -1 (GSD-1) called von Gierke's disease. Specifically mutations in the G6Pase- α lead to Glycogen Storage Disease Type-1a, which is characterized by is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. GSD-1a constitutes approximately 80% of GSD-1 cases that present clinically. Absence of G6PT leads to GSD-1b (GSD-1b), which is characterized by the lack of a G6PT and represents 20% of the cases that present clinically.

The specific cause of the GSD-1a stems from nonsense mutations, insertions/deletions with or without a shift in the reading frame, or splice site mutations that occur at the genetic level. The missense mutations affect the two large luminal loops and transmembrane helices of G6Pase-α, abolishing or greatly reducing activity of the enzyme. The specific cause of GSD-1b stems from "severe" mutations such as splice site mutations, frame-shifting mutations, and substitutions of a highly conserved residue that completely destroyed G6PT activity. These mutations lead to the prevalence of GSD-1 by preventing the transport of Glucose-6-phosphate (G6P) into the luminal portion of the ER and also inhibiting the conversion of G6P into glucose to be used by the cell.

The third type of Glucose-6-phosphatase deficiency, G6Pase- β deficiency, is characterized by a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. It can also lead to cardiac and urogenital malformations. This third class of deficiency is also affected by a G6PT deficiency as G6Pase- β also lies within the ER lumen and thus can lead to similar symptoms of G6Pase- β deficiency be associated with GSD-1b. Furthermore, recent studies have elucidated this area of similarity between both deficiencies and have shown that aberrant glycosylation occurs in both deficiencies. The neutrophil glycosylation has a profound effect on neutrophil activity and thus may also be classified as a congenital glycosylation disorder as well.

The major function of G6Pase- β has been determined to provide recycled glucose to the cytoplasm of neutrophils in order maintain normal function. Disruption of the of the glucose to G6P ratio due to significant decrease intracellular glucose levels cause significant disruption of glycolysis and HMS. Unless countered by uptake of extracellular glucose this deficiency leads to neutrophil dysfunction.