A GENE ON CHROMOSOME 11Q23 CODING FOR A PUTATIVE GLUCOSE-6-PHOSPHATE TRANSLOCASE IS MUTATED IN GLYCOGEN-STORAGE-DISEASE TYPES IB AND IC

Glycogen-storage diseases type I (GSD type I) are due to a deficiency in glucose-6-phosphatase, an enzymatic system present in the endoplasm ic reticulum that plays a crucial role in blood glucose homeostasis. U nlike GSD type Ia, types Tb and Ic are not due to mutations in the pho sphohydrolase gene and are clinically characterized by the presence of associated neutropenia and neutrophil dysfunction. Biochemical eviden ce indicates the presence of a defect in glucose-G-phosphate (GSD type Ib) or inorganic phosphate (Pi) (GSD type Ic) transport in the micros omes. We have recently cloned a cDNA encoding a putative glucose-G-pho sphate translocase. We have now localized the corresponding gene on ch romosome 11q23, the region where GSD types Ib and Ic have been mapped. Using SSCP analysis and sequencing, we have screened this gene, for m utations in genomic DNA, from patients from 22 different families who have GSD types Ib and Ic. Of 20 mutations found, 11 result in truncate d proteins that are probably nonfunctional. Most other mutations resul t in substitutions of conserved or semiconserved residues. The two mos t common mutations (Gly339Cys and 1211-1212 delCT) together constitute similar to 40% of the disease alleles. The fact that the same mutatio ns are found in GSD types Ib and Ic could indicate either that Pi and glucose-6-phosphate are transported in microsomes by the same transpor ter or that the biochemical assays used to differentiate Pi and glucos e-6-phosphate transport defects are not reliable.