Alternative titles; symbols
HGNC Approved Gene Symbol: SLC5A1
SNOMEDCT: 190749000, 27943000; ICD10CM: E74.39;
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:32,043,261-32,113,029 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Glucose/galactose malabsorption | 606824 | Autosomal recessive | 3 |
Glucose transporters are integral membrane proteins that mediate the transport of glucose and structurally-related substances across cellular membranes. Two families of glucose transporter have been identified: the facilitated-diffusion glucose transporter family (GLUT family), also known as 'uniporters,' and the sodium-dependent glucose transporter family (SGLT family), also known as 'cotransporters' or 'symporters.' The SLC5A1 gene encodes a protein that is involved in the active transport of glucose and galactose into eukaryotic and some prokaryotic cells (summary by Wright et al., 1994).
Hediger et al. (1987) determined the primary structure of the sodium/glucose cotransporter from rabbit small intestine by expression cloning and cDNA sequencing. Unexpectedly, the sodium/glucose cotransporter showed no homology with the facilitated glucose carrier (SLC2A1; 138140) or with bacterial sugar transport proteins. Thus, it was named the first member of a novel gene family, the SGLT1 family. Hediger et al. (1989) cloned and sequenced the human intestinal sodium/glucose transporter, SLC5A1. They found 95% similarity between the human and rabbit amino acid sequences. They determined that the human protein has 664 amino acids with a molecular mass of approximately 73 kD.
Northern blot analysis indicates that SLC5A1 mRNA is present mainly in intestine and kidney (Pajor and Wright, 1992). The SLC5A1 protein contains a core of 13 transmembrane domains, which it shares with other members of the gene family, and it contains an additional transmembrane appended to the C terminus (Turk and Wright, 1997). There is a heavily glycosylated site at asn248 (Hediger et al., 1991).
In a review of sodium/substrate symporter family proteins, Jung (2002) stated that human SGLT1 is an asymmetrical monomer containing 14 transmembrane domains, with the N terminus located on the periplasmic side of the membrane and the C terminus facing the cytoplasm.
Using confocal imaging analysis in human pancreas, Bonner et al. (2015) demonstrated that both SGLT1 and SGLT2 (SLC5A2; 182381) colocalize with glucagon in alpha cells, but not with insulin in beta cells. Western blot analysis confirmed the localization of SGLT1 and SGLT2 in human islet cells. Consistent with these results, mRNA from both SLC5A1 and SLC5A2 was more abundantly expressed in purified human alpha cells than in beta cells or dispersed islets. Immunofluorescence analysis confirmed that SGLT1 and SGLT2 proteins remained colocalized with glucagon in islets from both obese individuals and those with type 2 diabetes (125853).
Hediger et al. (1988) used a cDNA clone to probe human DNA and to map the human SLC5A1 gene. By Southern blot analysis of DNA from a panel of mouse-human hybrids, they demonstrated that only those hybrids containing chromosome 22 showed the characteristic bands identified by Southern analysis of human DNA. Hediger et al. (1989) mapped the SLC5A1 gene to 22q11.2-qter by study of DNA from somatic cell hybrids. A RFLP was identified with EcoRI. By fluorescence in situ hybridization, Turk et al. (1993) localized the gene to 22q13.1.
Turk et al. (1994) demonstrated that the SGLT1 gene contains 15 exons spanning 72 kb. Transcription initiation occurs from a site 27 bp 3-prime of a TATAA sequence. Sequence considerations and comparison of exons against protein secondary structure suggested a possible evolutionary origin of the SGLT1 gene from a 6-membrane-span ancestral precursor via a gene duplication event.
The intestinal sodium/glucose cotransporter is responsible for 'active' glucose absorption across the brush border membrane of the cells that line the gastrointestinal tract. This is an energy-requiring action that is driven by the sodium/potassium ATPase located at the basolateral cell membrane (Wright et al., 1994). The transepithelial absorption of glucose and galactose is then completed at the basal lateral membrane through the facilitated glucose transporter, which is similar if not identical to the 55-kD glucose carrier in erythrocytes (Mueckler et al., 1985).
In a review of sodium/substrate symporter family proteins, Jung (2002) stated that SGLT1 catalyzes uptake of Na+ and glucose with a 2:1 stoichiometry, coupled with the transport of 264 water molecules.
Margolskee et al. (2007) demonstrated that dietary sugar and artificial sweeteners increased intestinal SGLT1 mRNA and protein expression and increased glucose absorptive capacity in wildtype mice but not in knockout mice lacking the T1R2-T1R3 sweet taste receptor (see 606226) or alpha-gustducin (139395). In mouse GLUTag enteroendocrine cells, sucralose increased the release of GLP1 (see 138030) and GIP (137240), gut hormones implicated in SGLT1 upregulation, and increased intracellular calcium; inhibition of the T1R2-T1R3 sweet taste receptor by gurmarin blocked the sucralose-stimulated release of GLP1 and GIP and the sucralose-dependent mobilization of calcium in GLUTag cells.
Turk et al. (1991) identified a missense mutation (182380.0001) in the SLC5A1 gene in 2 related patients with glucose/galactose malabsorption (GGM; 606824). Martin et al. (1996) identified 31 novel mutations of SLC5A1 in 25 families with glucose/galactose malabsorption. In 16 families, the mutation was homozygous; 3 of these showed more than 1 mutation, including 1 kindred that had both homozygous and compound heterozygous mutations. Four mutations were found each in 2 presumably unrelated kindreds. There was a nonrandom distribution of missense mutations, with 8 such mutations in 2 conserved 'hotspots.' The finding established the protein encoded by SLC5A1 to be primarily responsible for intestinal uptake of glucose and galactose. See review by Wright et al., 1991.
In 33 patients from an extended Old Order Amish pedigree with GGM, Xin and Wang (2011) identified homozygosity for 4 nonsynonymous variants in the SLC5A1 gene that occurred on a founder haplotype. One of the variants (R558H; 182380.0003) had not previously been reported.
In 2 sisters with glucose/galactose malabsorption (GGM; 606824), Turk et al. (1991) demonstrated a G-to-A transition at nucleotide 92, resulting in substitution of asparagine for aspartic acid at amino acid 28 of the sodium/glucose cotransporter protein. The finding establishes the protein encoded by SGLT1 to be primarily responsible for intestinal uptake of glucose and galactose. Turk et al. (1994) corrected the location of the G-to-A transition mutation to be at nucleotide 105. The family in which Turk et al. (1994) demonstrated the D28N mutation was of Syrian descent. The parents were first cousins and the first affected child experienced severe diarrhea and dehydration starting on the first day of life. She was managed with a combination of formula and parenteral nutrition until about a year later, when a second sib was born with similar symptoms. The suspicion of GGM was confirmed by oral tolerance test, which revealed impairment of galactose and glucose absorption while that for xylose and fructose was normal. Glucose breath hydrogen test revealed severe malabsorption, while fructose was normal. Both children were free of diarrhea when on a glucose and galactose-restricted diet.
Martin et al. (1996) performed prenatal diagnosis in 2 subsequent pregnancies in a large consanguineous family using EcoRV restriction digestion. One showed that the fetus was heterozygous and the other showed that the fetus was not a carrier of the D28N mutation. Both children at 2 years of age remained healthy with no diarrhea.
Turk et al. (1994) described a missense mutation of the SGLT1 gene in a 4-year-old Lebanese child with first-cousin parents. The diagnosis of glucose/galactose malabsorption (GGM; 606824) was made after the child presented with severe diarrhea and dehydration. Intestinal absorption of D-glucose was severely impaired, while the absorption of D-fructose was normal. The mutation in the SGLT1 gene was an A-to-G transition at nucleotide 106 which led to an asp28-to-gly mutation.
In 33 patients from an extended Old Order Amish pedigree with glucose/galactose malabsorption (GGM; 606824), Xin and Wang (2011) identified a homozygous c.1673G-A transition in exon 14 of the SLC5A1 gene, resulting in an arg558-to-his (R558H) substitution at a highly conserved residue. The mutation, which segregated with the disorder in the families, was not found in a large control database. All patients were also homozygous for 3 additional nonsynonymous variants in the SLC5A1 gene: c.152A-G, resulting in an asn51-to-ser (N51S) substitution (rs17683011); c.1231G-A, resulting in an ala411-to-thr (A411T) substitution (rs17683430); and c.1845C-G, resulting in a his615-to-gln (H615Q) substitution (rs33954001). All 4 mutations segregated with the disorder in the families. Heterozygosity for the 4 mutations, which were present on a common haplotype, was found in 5% of Amish control alleles, indicating a founder effect. Xin and Wang (2011) noted that N51S occurred at a conserved residue and may also affect the protein. No functional studies were performed, and it was unclear how each individual mutation affected SLC5A1 protein function.
Bonner, C., Kerr-Conte, J., Gmyr, V., Queniat, G., Moerman, E., Thevenet, J., Beaucamps, C., Delalleau, N., Popescu, I., Malaisse, W. J., Sener, A., Deprez, B., Abderrahmani, A., Staels, B., Pattou, F. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nature Med. 21: 512-517, 2015. [PubMed: 25894829] [Full Text: https://doi.org/10.1038/nm.3828]
Hediger, M. A., Budarf, M. L., Emanuel, B. S., Mohandas, T. K., Wright, E. M. Assignment of the human intestinal Na+/glucose cotransporter gene (SGLT1) to the q11.2-qter region of chromosome 22. Genomics 4: 297-300, 1989. [PubMed: 2714793] [Full Text: https://doi.org/10.1016/0888-7543(89)90333-9]
Hediger, M. A., Coady, M. J., Ikeda, T. S., Wright, E. M. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature 330: 379-381, 1987. [PubMed: 2446136] [Full Text: https://doi.org/10.1038/330379a0]
Hediger, M. A., Coady, M. J., Mohandas, T., Shapiro, H. J., Wright, E. M. The human Na+/glucose cotransporter gene is located on chromosome 22. (Abstract) FASEB J. 2: A1021, 1988.
Hediger, M. A., Mendlein, J., Lee, H.-S., Wright, E. M. Biosynthesis of the cloned Na+/glucose. Biochim. Biophys. Acta 1064: 360-364, 1991. [PubMed: 1903656] [Full Text: https://doi.org/10.1016/0005-2736(91)90323-z]
Hediger, M. A., Turk, E., Wright, E. M. Homology of the human intestinal Na+/glucose and Escherichia coli Na+/proline cotransporters. Proc. Nat. Acad. Sci. 86: 5748-5752, 1989. [PubMed: 2490366] [Full Text: https://doi.org/10.1073/pnas.86.15.5748]
Jung, H. The sodium/substrate symporter family: structural and functional features. FEBS Lett. 529: 73-77, 2002. [PubMed: 12354616] [Full Text: https://doi.org/10.1016/s0014-5793(02)03184-8]
Margolskee, R. F., Dyer, J., Kokrashvili, Z., Salmon, K. S. H., Ilegems, E., Daly, K., Maillet, E. L., Ninomiya, Y., Mosinger, B., Shirazi-Beechey, S. P. T1R3 and gustducin in gut sense sugars to regulate expression of Na(+)-glucose cotransporter 1. Proc. Nat. Acad. Sci. 104: 15075-15080, 2007. [PubMed: 17724332] [Full Text: https://doi.org/10.1073/pnas.0706678104]
Martin, M. G., Turk, E., Kerner, C., Zabel, B., Wirth, S., Wright, E. M. Prenatal identification of a heterozygous status in two fetuses at risk for glucose-galactose malabsorption. Prenatal Diag. 16: 458-462, 1996. [PubMed: 8844006] [Full Text: https://doi.org/10.1002/(SICI)1097-0223(199605)16:5<458::AID-PD873>3.0.CO;2-U]
Martin, M. G., Turk, E., Lostao, M. P., Kerner, C., Wright, E. M. Defects in Na(+)/glucose cotransporter (SGLT1) trafficking and function cause glucose-galactose malabsorption. Nature Genet. 12: 216-220, 1996. [PubMed: 8563765] [Full Text: https://doi.org/10.1038/ng0296-216]
Mueckler, M., Caruso, C., Baldwin, S. A., Panico, M., Blench, I., Morris, H. R., Allard, W. J., Lienhard, G. E., Lodish, H. F. Sequence and structure of a human glucose transporter. Science 229: 941-945, 1985. [PubMed: 3839598] [Full Text: https://doi.org/10.1126/science.3839598]
Pajor, A., Wright, E. M. Cloning and functional expression of a mammalian Na+/nucleoside cotransporter: a member of the SGLT family. J. Biol. Chem. 267: 3557-3560, 1992. [PubMed: 1740408]
Turk, E., Klisak, I., Bacallao, R., Sparkes, R. S., Wright, E. M. Assignment of the human Na(+)/glucose cotransporter gene SGLT1 to chromosome 22q13.1. Genomics 17: 752-754, 1993. [PubMed: 8244393] [Full Text: https://doi.org/10.1006/geno.1993.1399]
Turk, E., Martin, M. G., Wright, E. M. Structure of the human Na+/glucose cotransporter gene SGLT1. J. Biol. Chem. 269: 15204-15209, 1994. [PubMed: 8195156]
Turk, E, Wright, E. M. Membrane topology motifs in the SGLT cotransporter family. J. Membr. Biol. 159: 1-20, 1997. [PubMed: 9309206] [Full Text: https://doi.org/10.1007/s002329900264]
Turk, E., Zabel, B., Mundlos, S., Dyer, J., Wright, E. M. Glucose/galactose malabsorption caused by a defect in the Na(+)/glucose cotransporter. Nature 350: 354-356, 1991. [PubMed: 2008213] [Full Text: https://doi.org/10.1038/350354a0]
Wright, E. M., Loo, D. D. F., Panayotova-Heiermann, M., Lostao, M. P., Hirayama, B. H., Mackenzie, B., Boorer, K., Zampighi, G. 'Active' sugar transport in eukaryotes. J. Exp. Biol. 196: 197-212, 1994. [PubMed: 7823022] [Full Text: https://doi.org/10.1242/jeb.196.1.197]
Wright, E. M., Turk, E., Zabel, B., Mundlos, S., Dyer, J. Molecular genetics of intestinal glucose transport. J. Clin. Invest. 88: 1435-1440, 1991. [PubMed: 1939637] [Full Text: https://doi.org/10.1172/JCI115451]
Xin, B., Wang, H. Multiple sequence variations in SLC5A1 gene are associated with glucose-galactose malabsorption in a large cohort of Old Order Amish. Clin. Genet. 79: 86-91, 2011. [PubMed: 20486940] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01440.x]