Alternative titles; symbols
HGNC Approved Gene Symbol: SLC2A2
SNOMEDCT: 61598006, 62332007;
Cytogenetic location: 3q26.2 Genomic coordinates (GRCh38) : 3:170,996,347-171,026,720 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.2 | {Diabetes mellitus, noninsulin-dependent} | 125853 | Autosomal dominant | 3 |
| Fanconi-Bickel syndrome | 227810 | Autosomal recessive | 3 |
Fukumoto et al. (1988) described cDNA clones encoding a glucose transporter-like protein isolated from adult human liver and kidney cDNA libraries. The predicted protein sequence of the 524-amino acid glucose transporter-like protein has 55.5% identity with the GLUT1 (138140) gene product. mRNA transcripts of 2.8, 3.4, and 5.4 kb were identified in human adult liver and, in much smaller quantities, in kidney and small intestine.
Permutt et al. (1989) described the cloning and functional expression of a glucose transporter cDNA isolated from human pancreatic islets. DNA sequence analysis indicated that the islet transporter is identical to the human liver-type glucose transporter polypeptide. They proposed that these cDNA clones can be used to study regulation of expression of the gene and to assess the role of inherited defects in the gene as the possible basis of inherited susceptibility to noninsulin-dependent diabetes mellitus (NIDDM; 125853). Because of its role in glucose signaling for beta-cell insulin release, Permutt et al. (1989) suggested that GLUT2 could be a candidate for an etiologic role in NIDDM.
Takeda et al. (1993) described the GLUT2 gene structure as consisting of 11 exons and 10 introns spanning approximately 30 kb.
Fukumoto et al. (1988) localized the gene, designated GLUT2, to human chromosome 3q26.1-q26.3 by somatic cell hybridization and in situ hybridization.
Matsutani et al. (1992) used a (CA)n dinucleotide repeat polymorphism adjacent to the 3-prime end of exon 4a for linkage studies and positioned the GLUT2 gene between markers D3S26 and D3S43 on 3q.
By immunocytochemical techniques, Orci et al. (1989) showed that the 'liver-type' glucose transporter is present in the insulin-producing beta cells of rat pancreatic islets but not in other islet endocrine cells. Furthermore, they showed that it is restricted to certain domains of the plasma membrane, its density being 6-fold higher in microvilli facing adjacent endocrine cells than in the flat regions of the plasma membrane. The findings suggested a role for this glucose transporter in glucose sensing by beta cells and provided evidence that these cells are polarized.
Thaiss et al. (2018) showed in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restored barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlated with individualized glycemic control, indicated by glycated hemoglobin levels. Thaiss et al. (2018) concluded that their results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.
Type 2 Diabetes Mellitus
Using GLUT2 and GLUT4 (138190) cDNA probes, Matsutani et al. (1990) evaluated DNA polymorphisms in genomic DNA from American blacks with type 2 diabetes mellitus (T2D; 601283). The allelic, genotypic, and haplotypic frequencies of the DNA polymorphisms at these loci did not differ from the frequencies in nondiabetic subjects. Because no associations with T2D were found, Matsutani et al. (1990) considered it unlikely that mutations at these loci contribute in a major way to genetic susceptibility to T2D in this population. Using the affected-pedigree-members statistical method, Baroni et al. (1992) could demonstrate no association between the TaqI RFLPs at the GLUT2 locus and T2D. No departure from independent segregation was observed. However, Mueckler et al. (1994) reported a mutation in the GLUT2 gene that abolished transport activity in a patient with type 2 diabetes mellitus; see 138160.0001.
In the Danish population, Moller et al. (2001) found no evidence supporting the hypothesis that genetic variability in the minimal promoter region of the GLUT2 gene is associated with type 2 diabetes or prediabetic phenotypes.
Fanconi-Bickel Syndrome
Santer et al. (1997) stated that Fanconi-Bickel syndrome (FBS; 227810) is the first genetic disorder known to be caused by a detectable genetic defect of one of the facilitative glucose transporters. Santer et al. (1997) reported 3 different homozygous GLUT2 mutations in 4 patients with FBS from 3 unrelated families; all parents tested were heterozygous for the respective mutation. Since the derived truncated translation products (138160.0002; 138160.0003; 138160.0004) cannot be expected to have functional monosaccharide transport activity, Santer et al. (1997) considered it likely that mutations in GLUT2 are the cause of Fanconi-Bickel syndrome. Several lines of evidence suggest that even if truncating mutations would not impair protein localization within the cell membrane, they would result in altered monosaccharide transport. First, the affected codon R365 is part of a highly conserved intracellular (R)XGRR motif common not only to the different facilitative glucose transporters but also to the sugar transport superfamily (Maiden et al., 1987). Second, the distal domain of glucose transport proteins, which in truncating mutations would be lost, has been shown to be essential for monosaccharide transport. According to the alternating conformation model of facilitative glucose transport, translocation of glucose across the cell membrane is thought to occur by a conformational change of the transporter between an inward-facing and an outward-facing substrate binding site. Holman (1989) proposed that these inner and outer glucose-binding sites are located in transmembrane segments 9, 10, and 11 of the GLUT protein. In vitro expression of GLUT mutants in different cell types have confirmed the importance of these segments. Missense mutations changing trp412 or asn415 of GLUT1, noted by Santer et al. (1997) as corresponding to trp444 and asn449 of the GLUT2 protein, respectively, severely impair glucose transport by modulating the inward-facing binding site (Katagiri et al., 1991; Garcia et al., 1992; Ishihara et al., 1991). Oka et al. (1990) demonstrated that a deletion mutant of GLUT1 lacking most of the carboxy-terminal intracellular domain had lost the ability to alternate its conformation and thus was functionally inactive. Third, Thorens et al. (1996) detected carboxy-terminal phosphorylation sites for a cAMP-dependent protein kinase, further emphasizing the role of the carboxy-terminal domain of the GLUT2 protein.
In a Japanese patient with Fanconi-Bickel syndrome, Akagi et al. (2000) found a homozygous nonsense mutation, trp420 to ter (138160.0006), in the SLC2A2 gene. In a second patient from a nonrelated Japanese family, no mutation was found in the entire protein coding region of the SLC2A2 gene.
Santer et al. (2002) stated that molecular genetic analysis had been performed in more than 50% of the 109 FBS cases from 88 families that they had been able to locate worldwide since the original report by Fanconi and Bickel (1949). They reported a total of 23 novel mutations of the SLC2A2 gene in 49 patients with a clinical diagnosis of FBS. In the 49 patients, 33 different SLC2A2 mutations (9 missense, 7 nonsense, 10 frameshift, 7 splice site) were detected. Mutations of SLC2A2 were detected in historic FBS patients (138160.0004) in whom some of the characteristic clinical features and the effect of therapy were described for the first time. Mutations were also found in patients with atypical clinical signs such as intestinal malabsorption, failure to thrive, absence of hepatomegaly, or renal hyperfiltration. No single prevalent SLC2A2 mutation was responsible for a significant number of cases. In a high proportion (74%) of FBS patients, the mutation was homozygous, suggesting that the prevalence of SLC2A2 mutations is low in most populations. No mutation hotspots within SLC2A2 or even within homologous sequences among the genes for facilitative glucose transporters were detected.
Sakamoto et al. (2000) studied 3 Japanese patients with Fanconi-Bickel syndrome and found 4 novel mutations in SLC2A2, including a splice site mutation, a nonsense mutation, and 2 missense mutations (138160.0012-138160.0015). Several family members who had a heterozygous missense mutation were shown to have glucosuria, but a family member heterozygous for the nonsense mutation did not. Sakamoto et al. (2000) speculated that mutant SLC2A2 proteins may have a dominant-negative effect and that heterozygosity for a nonsense mutation may not lead to glucosuria because of selective and efficient degradation of the nonsense mRNA.
GLUT2 is a low-affinity transporter present in the plasma membrane of pancreatic beta cells, hepatocytes, and intestine and kidney absorptive epithelial cells of mice. A role for GLUT2 in control of glucose-stimulated insulin secretion by pancreatic beta cells has been suggested. Guillam et al. (1997) showed that homozygous mice deficient in GLUT2 are hyperglycemic and relatively hypoinsulinemic and have elevated plasma levels of glucagon, free fatty acids, and beta-hydroxybutyrate. In vivo, their glucose tolerance was abnormal. In vitro, beta-cells displayed loss of control of insulin gene expression by glucose and impaired glucose-stimulated insulin secretion. This was accompanied by alterations in the postnatal development of pancreatic islets, evidenced by an inversion of the alpha- to beta-cell ratio. GLUT2 was thus demonstrated to be required to maintain normal glucose homeostasis and normal function and development of the endocrine pancreas. Its absence led to symptoms characteristic of noninsulin-dependent diabetes mellitus.
Efrat (1997) placed the work of Guillam et al. (1997) in perspective. Of the 6 known glucose transporters, each with its specialized function and tissue distribution, beta cells (as well as hepatocytes and epithelial cells of the kidney and intestine) express the type with the lowest affinity and the highest capacity for glucose, GLUT2. This allows beta cells to take up glucose effectively only in times of plenty, when insulin release is needed, and renders GLUT2 a prime suspect as the glucose sensor. Efrat (1997) concluded, however, that the extreme circumstance of total absence of GLUT2 in the knockout animal probably should not be taken as reinstating GLUT2 as a contender for the title of the beta-cell glucose sensor.
Tanizawa et al. (1994) reported 2 amino acid substitutions in the human GLUT2 gene: a thr110-to-ile substitution was present at equal frequency in diabetic and control populations, whereas a val197-to-ile substitution was discovered in a single allele of a patient with noninsulin-dependent diabetes (125853). Mueckler et al. (1994) tested the effect of these amino acid changes on glucose transport activity by expression of the mutant proteins in Xenopus oocytes. The polymorphism at threonine-110 had no effect on the expression of GLUT protein or the uptake of 2-deoxyglucose. On the other hand, the highly conserved val197-to-ile amino acid change abolished transport activity of the GLUT2 transporter expressed in Xenopus oocytes. This was the first known dysfunctional mutation in a human facilitative glucose transporter protein. The presence of the mutation in a diabetic patient suggested that defects in GLUT2 expression may be causally involved in the pathogenesis of noninsulin-dependent diabetes mellitus.
Santer et al. (2002) stated that the patient reported by Tanizawa et al. (1994) was a woman of African American descent with gestational diabetes mellitus and that the V197I mutation was heterozygous.
Santer et al. (1997) reported that the 2 Turkish sibs with Fanconi-Bickel syndrome (FBS; 227810) described by Muller et al. (1997) were homozygous for a single-base deletion in a stretch of 4 thymine residues (positions 446 to 449) in exon 3. This mutation caused a frameshift that predicted an aberrant transcription product with a premature TGA stop at codon 74 in the same exon, resulting in a truncated protein of 45 regular and 28 aberrant amino acids. If translated and transferred to the cell membrane, this truncated GLUT2 protein would have only 1 of 12 transmembrane segments, too small to form the hydrophilic tunnel for monosaccharide transport (Mueckler et al., 1985). Both consanguineous parents as well as one sister were heterozygous for this mutation. Santer et al. (1998) stated that this mutation had been found in 4 patients, including the original patient described by Fanconi and Bickel (1949), from 3 families.
Santer et al. (1997) described a Turkish boy with Fanconi-Bickel syndrome (FBS; 227810) who was homozygous for a C-to-T transition (CGA to TGA) at nucleotide 1405 in exon 8, causing a nonsense arg365-to-ter mutation (R365X); the mother was heterozygous for the C1405T mutation, as expected. The father was not available for analysis. The mutation predicts a truncated GLUT2 protein with only 8 of the 12 membrane-spanning segments.
Santer et al. (2002) stated that they had found the R365X mutation, which involves a CpG dinucleotide, in 4 unrelated families.
In a patient with Fanconi-Bickel syndrome (FBS; 227810) originally reported by Fanconi and Bickel (1949) and later by Gitzelmann (1957), Santer et al. (1997) described a homozygous C-to-T transition (CGA to TGA) at nucleotide 1213 in exon 6, causing a nonsense arg301-to-ter (R301X) mutation. (In an erratum to Santer et al. (1997), the authors pointed out that the transition as noted in the paper at nucleotide 1251 was incorrect, but that the amino acid mutation was correctly reported as R301X.) This change predicted a truncated GLUT2 protein with only 6 of the 12 membrane-spanning segments. At age 52 years, the patient was 140 cm tall and still lived in a remote valley of the southern Swiss Alps. He showed persistent clinical and chemical features of FBS. His consanguineous parents had died at ages 75 and 73 years; there was no evidence of diabetes mellitus (Steinmann and Zeller, 1997).
Santer et al. (2002) stated that they had found this mutation, which involves a CpG dinucleotide, in 4 unrelated families.
In 1 large family with a high degree of consanguinity and several affected individuals (both male and female), markedly reduced liver phosphorylase kinase activity was found in association with the characteristic clinical features and laboratory findings of Fanconi-Bickel syndrome (FBS; 227810) (Sanjad et al., 1993). This suggested that Fanconi-Bickel syndrome is genetically heterogeneous and that there may be another subtype of PHK deficiency (possibly associated with a distinctive genotype) that gives rise to hepatorenal glycogenosis. Burwinkel et al. (1999) showed that affected members of this family in fact had a homozygous missense mutation, pro417 to leu, in the GLUT2 gene. The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and is believed to be critical for the passage of glucose through the permease. Homozygosity for this mutation was found in 7 affected individuals from different branches of the same large consanguineous kindred. The low PHK activity was thought to be a secondary phenomenon that contributed to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency.
In a Japanese patient with Fanconi-Bickel syndrome (FBS; 227810), Akagi et al. (2000) found a homozygous G-to-A transition at nucleotide 1159 in exon 9 of the GLUT2 gene resulting in a nonsense mutation, trp420 to ter.
In 2 sibs of English ancestry with Fanconi-Bickel syndrome (FBS; 227810) described by Lee et al. (1995), Santer et al. (2002) identified compound heterozygosity for 1363delG and 1405C-T (138160.0008) mutations in the SLC2A2 gene. It was in these sibs that Lee et al. (1995) demonstrated the successful use of cornstarch in the management of this disorder.
For discussion of the 1405C-T mutation in the SLC2A2 gene that was found in compound heterozygous state in 2 sibs with Fanconi-Bickel syndrome (FBS; 227810) by Santer et al. (2002), see 138160.0007.
In 2 sibs of Turkish-Assyrian ancestry reported by Aperia et al. (1981), the presenting sign of Fanconi-Bickel syndrome (FBS; 227810) in infancy was failure to thrive because of intestinal malabsorption; hepatomegaly was absent. Santer et al. (2002) found that these sibs were homozygous for a splice acceptor site 1-bp insertion, 793-4insC.
In a white American infant with Fanconi-Bickel syndrome (FBS; 227810) and associated renal hyperfiltration reported by (Berry et al., 1995), Santer et al. (2002) found compound heterozygosity for 1264G-A and 469C-T (138160.0011) mutations in the SLC2A2 gene.
For discussion of the 469C-T mutation in the SLC2A2 gene that was found in compound heterozygous state in a patient with Fanconi-Bickel syndrome (FBS; 227810) by Santer et al. (2002), see 138160.0010.
In a Japanese patient with Fanconi-Bickel syndrome (FBS; 227810), Sakamoto et al. (2000) found homozygosity for a 1580T-A change in the SLC2A2 gene, resulting in a val423-to-glu (V423E) substitution. The patient's father, mother, and brother were heterozygous for this mutation. The brother had been found to have glucosuria on a preemployment physical with a normal oral glucose tolerance test. The mother had sometimes shown postprandial glucosuria in addition to having a borderline oral glucose tolerance test. The father did not have glucosuria and had a normal oral glucose tolerance test. The mutation was not found in 50 healthy volunteers.
In a Japanese patient with Fanconi-Bickel syndrome (FBS; 227810) and mental retardation, Sakamoto et al. (2000) identified a homozygous A-to-G substitution at position -2 of the splice acceptor site of intron 2 of the SLC2A2 gene, causing skipping of exon 3 and resulting in a frameshift and creation of a premature termination codon. The patient's mother was heterozygous for the mutation, but the father could not be studied.
In a Japanese patient diagnosed with Fanconi-Bickel syndrome (FBS; 227810) after hypergalactosemia was detected by neonatal screening, Sakamoto et al. (2000) found compound heterozygosity for 2 mutations in the SLC2A2 gene: a 1171C-T transition in exon 6, resulting in a gln287-to-ter (Q287X) substitution, inherited from the father, and a 1478T-C transition in exon 8, resulting in a leu389-to-pro (L389P; 138160.0015) substitution, inherited from the mother. The father did not have glucosuria, but the mother had glucosuria with a normal oral glucose tolerance test. Neither mutation was found in 50 healthy volunteers.
For discussion of the leu389-to-pro (L389P) mutation in the SLC2A2 gene that was found in compound heterozygous state in a patient with Fanconi-Bickel syndrome (FBS; 227810) by Sakamoto et al. (2000), see 138160.0014.
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