MUTATIONS IN THE GLUCOSE-6-PHOSPHATASE GENE ARE ASSOCIATED WITH GLYCOGEN-STORAGE-DISEASE TYPES 1A AND 1ASP BUT NOT 1B AND 1C

Glycogen storage disease (GSD) type 1, which is caused by the deficien cy of glucose-6-phosphatase (G6Pase), is an autosomal recessive diseas e with heterogenous symptoms, Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-cat alytic unit model proposes that five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), a nd glucose (1d) translocases. Conversely, the conformation-substrate-t ransport model suggests that G6Pase is a single multifunctional membra ne channel protein possessing both catalytic and substrate (or product ) transport activities, We have recently demonstrated that mutations i n the G6Pase catalytic unit cause GSD type 1a. To elucidate whether mu tations in the G6Pase gene are responsible for other GSD type 1 subgro ups, we characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP pat ients, Our results show that the G6Pase gene of GSD type 1b and 1c pat ients is normal, consistent with the translocase-catalytic unit model of G6Pase catalysis. However, a mutation in exon 2 that converts an Ar g at codon 83 to a Cys (R83C) was identified in both G6Pase alleles of the type 1aSP patient. The R83C mutation was also demonstrated in one homozygous and five heterogenous GSD type la patients, indicating tha t type 1aSP is a misclassification of GSD type 1a. We have also analyz ed the G6Pase gene of seven additional type 1a patients and uncovered two new mutations that cause GSD type 1a.