The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic

Glycogen storage disease type Ib (GSD-Ib) is caused by deficiencies in the glucose-6-phosphate (G6P) transporter (G6PT) that have been well characterized. Interestingly, deleterious mutations in the G6PT gene were identified in clinical cases of GSD type Ic (GSD-Ic) proposed to be deficient in an inorganic phosphate (P-i) transporter. We hypothesized that G6PT is both the G6P and Pi transporter. Using reconstituted proteoliposomes we show that both G6P and P-i are efficiently taken up into P-i-loaded G6PT-proteoliposomes. The G6P uptake activity decreases as the internal: external P-i ratio decreases and the P-i uptake activity decreases in the presence of external G6P. Moreover, G6P or P-i uptake activity is not detectable in P-i-loaded proteoliposomes containing the p.R28H G6PT null mutant. The G6PT-proteoliposome-mediated G6P or P-i uptake is inhibited by cholorgenic acid and vanadate, both specific G6PT inhibitors. Glucose-6-phosphatase-alpha (G6Pase-alpha), which facilitates microsomal G6P uptake by G6PT, fails to stimulate G6P uptake in P-i-loaded G6PT-proteoliposomes, suggesting that the G6Pase-alpha-mediated stimulation is caused by decreasing G6P and increasing P-i concentrations in microsomes. Taken together, our results suggest that G6PT has a dual role as a G6P and a P-i transporter and that GSD-Ib and GSD-Ic are deficient in the same G6PT gene.