Disease relevance of SLC37A4

• Glycogen storage disease type 1b is caused by a deficiency in a glucose 6-phosphate transporter (G6PT) that translocates glucose 6-phosphate from the cytoplasm to the endoplasmic reticulum lumen where the active site of glucose 6-phosphatase is situated [1].
• These results also suggest that G6PT operates by a similar antiport mechanism as its E. coli homologue, namely, the substrate binds at the N- and C-terminal domain interface and is then transported across the membrane via a rocker-switch type of movement of the two domains [2].
• The G6PT1 gene was strongly expressed in liver, kidney and haematopoietic progenitor cells, which might explain major clinical symptoms such as hepatomegaly, nephromegaly and neutropenia in glycogen storage diseases type Ib [3].
• Silencing of the human microsomal glucose-6-phosphate translocase induces glioma cell death: potential new anticancer target for curcumin [4].
• The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression [5].

Psychiatry related information on SLC37A4

• Investigation of patients with GSD I shows that those with GSD Ia are mutated in the glucose-6-phosphate hydrolase gene, whereas those diagnosed as GSD Ib, GSD Ic or GSD Id are mutated in the glucose-6-phosphate translocase gene, and are therefore GSD Ib patients, in agreement with the fact that they all have neutropenia or neutrophil dysfunction [6].

High impact information on SLC37A4

• Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b) [7].
• Current understanding of neutrophil apoptosis and the accompanying functional demise suggests that GSD1b granulocytes are dysfunctional because they are apoptotic [7].
• Moreover, the 2 GSD1b patients on G-CSF treatment did not show significantly lower levels of apoptotic neutrophils in the bloodstream [7].
• In 5 GSD1b patients in whom nicotin-amide adenine dinucleotide phosphate-oxidase activity and chemotaxis were defective, we found that the majority of circulating granulocytes bound Annexin-V [7].
• Glycogen storage disease type 1b (GSD1b) is a rare autosomal recessive disorder characterized by hypoglycemia, hepatomegaly, and growth retardation, and associated-for unknown reasons- with neutropenia and neutrophil dysfunction [7].

Chemical compound and disease context of SLC37A4

• The anticancer agent curcumin, also inhibited G6PT gene expression by more than 90% and triggered U-87 glioma cells death [4].
• Glycogen storage diseases type I (GSD I) are a group of metabolic disorders arising from a defect in a component of this enzymatic system, i.e. the glucose-6-phosphate hydrolase (GSD Ia), the glucose-6-phosphate translocase (GSD Ib) and possibly also the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id) [6].
• 1. Type 1b and type 1c glycogen-storage disease are caused respectively by deficiencies of the glucose-6-phosphate translocase and the phosphate/pyrophosphate translocase of the human hepatic microsomal glucose-6-phosphatase system [8].

Biological context of SLC37A4

• G6Pase and G6PT work in concert to maintain glucose homeostasis in gluconeogenic organs [9].
• Rapid confirmation of clinically suspected diagnosis of GSD 1, reliable carrier testing, and prenatal diagnosis are facilitated by mutation analyses of the chromosome 11-bound G6PT gene as well as the chromosome 17-bound G6Pase gene [9].
• Whereas G6Pase is exclusively expressed in gluconeogenic cells, G6PT is ubiquitously expressed and its deficiency generally causes a more severe phenotype [9].
• A mRNA leucocyte G6PT deficiency has been suggested to account for the glucose phosphorylation and subsequent calcium sequestration defects observed in theses cells [10].
• Here, we report on the analysis by single-stranded conformation polymorphism (SSCP) and/or DNA sequencing of the exons of the G6PT in 14 patients diagnosed either as affected by the GSD 1b or 1c subtypes [11].

Anatomical context of SLC37A4

• Both G6Pase and G6PT are associated with the endoplasmic reticulum (ER) membrane [12].
• Using amino- and carboxyl-terminal tagged G6PT, we demonstrate that proteolytic digestion of intact microsomes resulted in the cleavage of both tags, indicating that both termini of G6PT face the cytoplasm [1].
• Quantitative analysis of glucose-6-phosphate translocase gene expression in various human tissues and haematopoietic progenitor cells [3].
• Further, we show that G6PT mRNA is expressed in all organs and tissues examined, but that the vG6PT transcript is expressed exclusively in the brain, heart, and skeletal muscle [13].
• Conversely, expression of both the mouse homologue of the previously-described brain-specific G6P translocase T1 (G6PT1) variant and of the hepatic G6PT1 isoform was easily detectable in hypothalamus and cortex tissues [14].

Associations of SLC37A4 with chemical compounds

• GSD 1 non-a is characterized by defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport due to mutations in G6PT (glucose-6-phosphate translocase gene) encoding a microsomal transporter protein [9].
• It was suggested that GSD1b patients suffered from a G6P transporter (G6PT) defect and the first mutation in the G6PT gene subsequently recognised [10].
• To determine which of these two models is correct, we generated two G6PT mutants, T53N and S55N, that created a potential Asn-linked glycosylation site at residues 53-55 (N53SS) or 55-57 (N55QS), respectively [1].
• A region of G6PT corresponding to amino acid residues 50-71, which constitute a transmembrane segment in the twelve-domain model, are situated in a 51-residue luminal loop in the ten-domain model [1].
• Whereas wild-type G6PT is not a glycoprotein, both T53N and S55N mutants are glycosylated, strongly supporting the ten-helical model for G6PT [1].

Other interactions of SLC37A4

• The genes encoding G6Pase and the glucose 6-phosphate translocase have been cloned and shown to be mutated in glycogen storage disease type Ia and type Ib respectively [15].
• Our data suggest that neutrophil dysfunction in GSD1b patients might be related to functional impairment and disorganization of proteins of the sub-membrane apparatus, and that G-CSF treatment counteracts neutropenia and prevents the progressive alterations of neutrophil sub-membrane proteins [16].
• Here, we generated a three-dimensional model for Glut1 using a two-step strategy: 1), GlpT structure as an initial homology template and 2), evolutionary homology using glucose-6-phosphate translocase as a template [17].

Analytical, diagnostic and therapeutic context of SLC37A4

• Reverse transcriptase-mediated PCR amplification of G6PT1 cDNA revealed several splicing variants in tissue-specific manners [3].
• Current laboratory diagnosis for GSD1b is established by a functional enzyme assay of glucose-6-phosphatase in both fresh and detergent-treated liver homogenates [18].
• Assignment1 of glucose 6-phosphate translocase (G6PT1) to human chromosome band 11q23.3 by in situ hybridization [19].
• Flow cytometry analysis of propidium iodide/annexin-V-stained cells indicated that silencing the G6PT gene induced necrosis and late apoptosis [4].
• It is as yet unclear whether hepatic secretion of lipids in the form of very low density lipoprotein-triglycerides (VLDL-TG) is altered in GSD1 patients: we recently found unaffected VLDL-TG secretion rates in an acute animal model of GSD1b [20].

References