A Gene on Chromosome 11q23 Coding for a Putative Glucose- 6-Phosphate Translocase Is Mutated in Glycogen-Storage Disease Types Ib and Ic

Abstract

Glycogen-storage diseases type I (GSD type I) are due to a deficiency in glucose-6-phosphatase, an enzymatic system present in the endoplasmic reticulum that plays a crucial role in blood glucose homeostasis. Unlike GSD type Ia, types Ib and Ic are not due to mutations in the phosphohydrolase gene and are clinically characterized by the presence of associated neutropenia and neutrophil dysfunction. Biochemical evidence indicates the presence of a defect in glucose-6-phosphate (GSD type Ib) or inorganic phosphate (Pi) (GSD type Ic) transport in the microsomes. We have recently cloned a cDNA encoding a putative glucose-6-phosphate translocase. We have now localized the corresponding gene on chromosome 11q23, the region where GSD types Ib and Ic have been mapped. Using SSCP analysis and sequencing, we have screened this gene, for mutations in genomic DNA, from patients from 22 different families who have GSD types Ib and Ic. Of 20 mutations found, 11 result in truncated proteins that are probably nonfunctional. Most other mutations result in substitutions of conserved or semiconserved residues. The two most common mutations (Gly339Cys and 1211-1212 delCT) together constitute approximately 40% of the disease alleles. The fact that the same mutations are found in GSD types Ib and Ic could indicate either that Pi and glucose-6-phosphate are transported in microsomes by the same transporter or that the biochemical assays used to differentiate Pi and glucose-6-phosphate transport defects are not reliable.

Overexpression of the P46 (T1) Translocase Component of the Glucose-6-phosphatase Complex in Hepatocytes Impairs Glycogen Accumulation via Hydrolysis of Glucose 1-Phosphate

“…The transcript corresponding to the putative P46 clone was found to be expressed at highest levels in liver and kidney, consistent with a role in the gluconeogenic glucose-6-phosphatase complex. The strongest evidence that the newly cloned gene was a component of the mammalian glucose-6-phosphatase enzyme complex was the identification of mutations in the gene in two human subjects with type 1b glycogen storage disease (11). However, the precise biochemical function of P46 in mammalian cells has not been elucidated.…”

“…Mutations in P36 and P46 have both been linked to glycogen storage diseases in human subjects (5,11). Patients with type Ia glycogen storage disease have mutations in the P36 gene (5) and a complete deficiency of glucose-6-phosphatase enzymatic activity, regardless of whether the assay is performed in intact or detergent-disrupted microsomal preparations (12).…”

“…Patients with type Ia glycogen storage disease have mutations in the P36 gene (5) and a complete deficiency of glucose-6-phosphatase enzymatic activity, regardless of whether the assay is performed in intact or detergent-disrupted microsomal preparations (12). Patients with type Ib glycogen storage disease have mutations in the P46 gene (11) and have absent or reduced glucose-6-phosphatase enzymatic activity in intact microsomes but normal or increased activity in detergent-disrupted preparations (13).…”

Identification of protein components of the microsomal glucose 6-phosphate transporter by photoaffinity labelling

“…In patient 1, a point mutation Gly$$* Cys as well as a mutation replacing Glu$$& by a stop codon was found, whereas in patient 2 only a point mutation Gly$$* Cys was reported [22]. A recent publication in which the amino acid sequence of the putative glucose-6-phosphate translocase was analysed in 22 patients with diagnosed GSD type 1b or type 1c revealed mutations in this gene, strengthening its putative role as glucose-6-phosphate translocase [40]. However, the functional link between the gene product and the transport of glucose 6-phosphate has not yet been reported.…”

Glucose 6-phosphate transport in fibroblast microsomes from glycogen storage disease type 1b patients: evidence for multiple glucose 6-phosphate transport systems

“…The genetic deficiency of this G6P transport activity causes a severe metabolic disease termed type 1b glycogen storage disease (GSD1b) [4]. A gene encoding a putative liver ER transporter for G6P (G6PT1) was cloned [5] and shown to be mutated in patients suffering from GSD1b [5][6][7][8][9][10][11][12][13]. In this disease the major tissue damage is present in liver and kidney, consistent with the high representation of the G6Pase system in these organs [14].…”