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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 deficiency of glucose-6-phosphatase (G6Pase), is an autosomal recessive disease with heterogenous symptoms. Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-catalytic unit model pr...

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Published in:The Journal of clinical investigation 1995-01, Vol.95 (1), p.234-240
Main Authors: Lei, K J, Shelly, L L, Lin, B, Sidbury, J B, Chen, Y T, Nordlie, R C, Chou, J Y
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container_title The Journal of clinical investigation
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Shelly, L L
Lin, B
Sidbury, J B
Chen, Y T
Nordlie, R C
Chou, J Y
description Glycogen storage disease (GSD) type 1, which is caused by the deficiency of glucose-6-phosphatase (G6Pase), is an autosomal 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 (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), and glucose (1d) translocases. Conversely, the conformation-substrate-transport model suggests that G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities. We have recently demonstrated that mutations in the G6Pase catalytic unit cause GSD type 1a. To elucidate whether mutations in the G6Pase gene are responsible for other GSD type 1 subgroups, we characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP patients. Our results show that the G6Pase gene of GSD type 1b and 1c patients is normal, consistent with the translocase-catalytic unit model of G6Pase catalysis. However, a mutation in exon 2 that converts an Arg 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 1a patients, indicating that type 1aSP is a misclassification of GSD type 1a. We have also analyzed the G6Pase gene of seven additional type 1a patients and uncovered two new mutations that cause GSD type 1a.
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subjects Alleles
Amino Acid Sequence
Base Sequence
Cells, Cultured
Cloning, Molecular
Genome, Human
Glucose-6-Phosphatase - genetics
Glycogen Storage Disease Type I - classification
Glycogen Storage Disease Type I - enzymology
Glycogen Storage Disease Type I - genetics
Heterozygote
Homozygote
Humans
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Mutation - genetics
Polymerase Chain Reaction
Sequence Analysis, DNA
Transfection
title Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c
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