Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c.

Abstract

Glycogen storage disease (GSD) type 1, which is caused by the deficiency of glucose-6-phosphatase (G6Pase), is an au- tosomal recessive disease with heterogenous symptoms. Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-catalytic unit model proposes that five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (la), a stabilizing protein (laSP), the glucose-6-P (lb), phosphate/ pyrophosphate (ic), and glucose (id) translocases. Con- versely, the conformation-substrate-transport model sug- gests that G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities. We have recently demon- strated that mutations in the G6Pase catalytic unit cause GSD type la. To elucidate whether mutations in the G6Pase gene are responsible for other GSD type 1 subgroups, we characterized the G6Pase gene of GSD type lb, ic, and laSP patients. Our results show that the G6Pase gene of GSD type lb and lc patients is normal, consistent with the translocase- catalytic unit model of G6Pase catalysis. However, a muta- tion in exon 2 that converts an Arg at codon 83 to a Cys (R83C) was identified in both G6Pase alleles of the type laSP patient. The R83C mutation was also demonstrated in one homozygous and five heterogenous GSD type la pa- tients, indicating that type laSP is a misclassification of GSD type la. We have also analyzed the G6Pase gene of seven additional type la patients and uncovered two new muta- tions that cause GSD type la. (