Type Ib glycogen storage disease is caused by a defect in the glucose-6-phosphate translocase of the microsomal glucose-6-phosphatase system

Glucose-6-phosphate activity of liver and kidney microsomes with intact limiting membranes (i.e., intact microsomes) requires the coupling of three integral membrane components: a glucose-6-P-specific translocase (T₁), a nonspecific phosphohydrolase located on the luminal surface of the membrane, and a phosphate translocase (T₂) that mediates P(i) efflux (Arion, W.J., Lange, A.J., Walls, H.E., and Ballas, L.M. (1980) J. Biol. Chem. 255, in press). Since T₂ also mediates penetration of inorganic pyrophosphate (PP(i)) into microsomes, T₂ and enzyme constitute the functional pyrophosphate (PP(i)ase) activity of intact microsomes. Type I glycogen storage disease is caused by a deficiency of glucose-6-phosphatase. Two subtypes of the type I disorder are known: type Ia with deficient glucose-6-phosphatase and type Ib with apparent normal glucose-6-phosphatase in frozen tissue biopsy specimens. The present study sought to identify the defect in type Ib glycogen storage disease. Glucose-6-phosphatase and PP(i)ase were characterized in liver microsomes prepared from fresh (unfrozen) liver obtained by surgical biopsy from a type Ib patient, a patient with type III glycogen storage disease, and a normal control. Intact microsomes from the type Ib patient were devoid of glucose-6-phosphatase activity despite the presence of higher than normal glucose-6-phosphatase activity in microsomes lacking selective permeability (i.e. disrupted microsomes). PP(i)ase activity of intact microsomes from the type Ib patient was greater than that of the other preparations. The results clearly demonstrate a defect in T₁ in the hepatic endoplasmic reticulum of type Ib glycogen storage disease patients. Findings of 'normal' glucose-6-phosphatase in biopsy specimens from these patients reflect destruction of the microsomal permeability barrier as a result of freezing the tissue prior to assay. Glucose-6-P transport into the lumen of the endoplasmic reticulum of hepatocytes, neutrophils, and possibly other cell types may be essential for metabolic processes unrelated to glucose-6-P hydrolysis.