Skip to main content
SpringerLink
Log in

Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Vitamin C (L-ascorbic acid) is an essential co-factor for eight mammalian enzymes and quenches reactive oxygen species. Sodium-dependent vitamin C transport is mediated by two transporters, SVCT 1 and SVCT 2, encoded by SLC23A1 and SLC23A2. We characterized the genomic structures of SLC23A1 and SLC23A2, determined the extent of genetic variation and linkage disequilibrium across each gene, analyzed nucleotide diversity to estimate the effect of selective pressure, and compared sequence variation across species. In SLC23A1, the majority of single nucleotide polymorphisms (SNPs) are population-specific in either African Americans or Caucasians, including three of four non-synonymous SNPs. In contrast, most SNPs in SLC23A2 are shared between African Americans and Caucasians, and there are no non-synonymous SNPs in SLC23A2. Our analysis, combined with previous in vitro and in vivo studies, suggests that non-synonymous variation appears to be tolerated in SLC23A1 but not SLC23A2, and that this may be a consequence of different selective pressures following past gene duplication of the sodium-dependent vitamin C transporters. Genetic association studies of these two genes will need to account for the differences in haplotype structure and the population-specific variants. Our data represent a fundamental step toward the application of genetics to refining nutrient recommendations, specifically for vitamin C, and may serve as a paradigm for other vitamins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2A, B
Fig. 3

Similar content being viewed by others

Notes

  1. In 2002, the official HUGO gene names were changed so that SLC23A1 corresponds to SVCT1 and SLC23A2 corresponds to SVCT2.

References

  • Burset M, Seledtsov IA, Solovyev VV (2000) Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res 28:4364–4375

    Article  CAS  PubMed  Google Scholar 

  • Carlson CS, Eberle MA, Rieder MJ, Smith JD, Kruglyak L, Nickerson DA (2003) Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet 33:518–521

    Article  CAS  PubMed  Google Scholar 

  • Collins FS (1999) Shattuck lecture—medical and societal consequences of the Human Genome Project. N Engl J Med 341:28–37

    Article  CAS  PubMed  Google Scholar 

  • Daruwala R, Song J, Koh WS, Rumsey SC, Levine M (1999) Cloning and functional characterization of the human sodium-dependent vitamin C transporters hSVCT1 and hSVCT2. FEBS Lett 460:480–484

    Google Scholar 

  • Dhariwal KR, Hartzell WO, Levine M (1991) Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum. Am J Clin Nutr 54:712–716

    CAS  PubMed  Google Scholar 

  • Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12:205–216

    Article  CAS  PubMed  Google Scholar 

  • Dubchak I, Brudno M, Loots GG, Pachter L, Mayor C, Rubin EM, Frazer KA (2000) Active conservation of noncoding sequences revealed by three-way species comparisons. Genome Res 10:1304–1306

    Article  CAS  PubMed  Google Scholar 

  • Erichsen HC, Eck P, Levine M, Chanock S (2001) Characterization of the genomic structure of the human vitamin C transporter SVCT1 (SLC23A2). J Nutr 131:2623–2627

    CAS  PubMed  Google Scholar 

  • Food and Nutrition Board PoDAaRC (2000) Vitamin C. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. National Academy Press, Washington DC, pp 1–185

    Google Scholar 

  • Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709

    CAS  PubMed  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  CAS  PubMed  Google Scholar 

  • Kruglyak L, Nickerson DA (2001) Variation is the spice of life. Nat Genet 27:234–236

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Hedges SB (1998) A molecular timescale for vertebrate evolution. Nature 392:917–920

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Tamura K, Jakobsen IB, Nei M (2001) MEGA2: molecular evolutionary genetics analysis software. Bioinformatics 17:1244–1245

    Article  CAS  PubMed  Google Scholar 

  • Leabman MK, Huang CC, DeYoung J, Carlson EJ, Taylor TR, Cruz M de la, Johns SJ, Stryke D, Kawamoto M, Urban TJ, Kroetz DL, Ferrin TE, Clark AG, Risch N, Herskowitz I, Giacomini KM (2003) Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc Natl Acad Sci USA 100:5896–5901

    Article  CAS  PubMed  Google Scholar 

  • Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR (1996) Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci USA 93:3704–3709

    Article  CAS  PubMed  Google Scholar 

  • Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y (1999) Criteria and recommendations for vitamin C intake. JAMA 281:1415–1423

    Article  CAS  PubMed  Google Scholar 

  • Levine M, Wang Y, Padayatty SJ, Morrow J (2001) A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci USA 98:9842–9846

    Article  CAS  PubMed  Google Scholar 

  • Mayor C, Brudno M, Schwartz JR, Poliakov A, Rubin EM, Frazer KA, Pachter LS, Dubchak I (2000) VISTA: visualizing global DNA sequence alignments of arbitrary length. Bioinformatics 16:1046–1047

    Article  CAS  PubMed  Google Scholar 

  • Nishikimi M, Fukuyama R, Minoshima S, Shimizu N, Yagi K (1994) Cloning and chromosomal mapping of the human nonfunctional gene for l-gulono-gamma-lactone oxidase, the enzyme for l-ascorbic acid biosynthesis missing in man. J Biol Chem 269:13685–13688

    Google Scholar 

  • Ota T, Nei M (1994) Estimation of the number of amino acid substitutions per site when the substitution rate varies among sites. J Mol Evol 38:642–643

    Google Scholar 

  • Packer BR, Yeager M, Staats B, Welch R, Crenshaw A, Kiley M, Eckert A, Beerman M, Miller E, Bergen A, Rothman N, Strausberg R, Chanock SJ (2004) SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes. Nucleic Acids Res 32:D528–D532

    Article  CAS  Google Scholar 

  • Reich DE, Gabriel SB, Altshuler D (2003) Quality and completeness of SNP databases. Nat Genet 33:457–458

    Article  CAS  PubMed  Google Scholar 

  • Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405:847–856

    Article  CAS  PubMed  Google Scholar 

  • Rumsey SC, Kwon O, Xu GW, Burant CF, Simpson I, Levine M (1997) Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid. J Biol Chem 272:18982–18989

    Article  CAS  PubMed  Google Scholar 

  • Rumsey SC, Welch RW, Garraffo HM, Ge P, Lu SF, Crossman AT, Kirk KL, Levine M (1999) Specificity of ascorbate analogs for ascorbate transport. Synthesis and detection of [(125)I]6-deoxy-6-iodo-L-ascorbic acid and characterization of its ascorbate-specific transport properties. J Biol Chem 274:23215–23222

    Article  CAS  PubMed  Google Scholar 

  • Rumsey SC, Daruwala R, Al-Hasani H, Zarnowski MJ, Simpson IA, Levine M (2000) Dehydroascorbic acid transport by GLUT4 in Xenopus oocytes and isolated rat adipocytes. J Biol Chem 275:28246–28253

    CAS  PubMed  Google Scholar 

  • Rzhetsky A, Nei M (1992) A simple method for estimating and testing minimum-evolution trees. Mol Biol Evol 9:945–967

    CAS  Google Scholar 

  • Sotiriou S, Gispert S, Cheng J, Wang Y, Chen A, Hoogstraten-Miller S, Miller GF, Kwon O, Levine M, Guttentag SH, Nussbaum RL (2002) Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat Med 8:514–517

    Article  CAS  PubMed  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  CAS  PubMed  Google Scholar 

  • Stram DO, Leigh-Pearce C, Bretsky P, Freedman M, Hirschhorn JN, Altshuler D, Kolonel L, Henderson BE, Thomas DC (2003) Modeling and E-M estimation of haplotype-specific risks from genotype data for a case-control study of unrelated individuals. Hum Hered 55:179–190

    Article  Google Scholar 

  • Stratakis CA, Taymans SE, Daruwala R, Song J, Levine M (2000) Mapping of the human genes (SLC23A2 and SLC23A1) coding for vitamin C transporters 1 and 2 (SVCT1 and SVCT2) to 5q23 and 20p12, respectively. J Med Genet 37:E20

    Article  CAS  PubMed  Google Scholar 

  • Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595

    CAS  PubMed  Google Scholar 

  • Taylor JG, Choi EH, Foster CB, Chanock SJ (2001) Using genetic variation to study human disease. Trends Mol Med 7:507–512

    Article  CAS  PubMed  Google Scholar 

  • Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680

    CAS  PubMed  Google Scholar 

  • Tsukaguchi H, Tokui T, Mackenzie B, Berger UV, Chen XZ, Wang Y, Brubaker RF, Hediger MA (1999) A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature 399:70–75

    Article  CAS  PubMed  Google Scholar 

  • Vera JC, Rivas CI, Fischbarg J, Golde DW (1993) Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 364:79–82

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Russo TA, Kwon O, Chanock S, Rumsey SC, Levine M (1997) Ascorbate recycling in human neutrophils: induction by bacteria. Proc Natl Acad Sci USA 94:13816–13819

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Dutta B, Huang W, Devoe LD, Leibach FH, Ganapathy V, Prasad PD (1999) Human Na(+)-dependent vitamin C transporter 1 (hSVCT1): primary structure, functional characteristics and evidence for a non-functional splice variant. Biochim Biophys Acta 1461:1–9

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Mackenzie B, Tsukaguchi H, Weremowicz S, Morton CC, Hediger MA (2000) Human vitamin C (l-ascorbic acid) transporter SVCT1. Biochem Biophys Res Commun 267:488–494

    Article  CAS  PubMed  Google Scholar 

  • Washko PW, Wang Y, Levine M (1993) Ascorbic acid recycling in human neutrophils. J Biol Chem 268:15531–15535

    CAS  PubMed  Google Scholar 

  • Williams RJ, Deason G (1967) Individuality in vitamin C needs. Proc Natl Acad Sci USA 57:1638–1641

    CAS  PubMed  Google Scholar 

  • Williams RJ, Pelton RB (1966) Individuality in nutrition: effects of vitamin A-deficient and other deficient diets on experimental animals. Proc Natl Acad Sci USA 55:126–134

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

    Peter Eck & Mark Levine

  2. Section on Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, Advanced Technology Center, National Institutes of Health, 8717 Grovemont Circle, Gaithersburg, MD 20892-4605, USA

    Hans Christian Erichsen, James G. Taylor & Stephen J. Chanock

  3. Intramural Research Support Program, SAIC Frederick, NCI-FCRDC, Frederick, MD 21702, USA

    Meredith Yeager

  4. Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA

    Austin L. Hughes

Authors
  1. Peter Eck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Christian Erichsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James G. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meredith Yeager
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Austin L. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen J. Chanock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen J. Chanock.

Additional information

Peter Eck and Hans Christian Erichsen contributed equally to this manuscript

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eck, P., Erichsen, H.C., Taylor, J.G. et al. Comparison of the genomic structure and variation in the two human sodium-dependent vitamin C transporters, SLC23A1 and SLC23A2. Hum Genet 115, 285–294 (2004). https://doi.org/10.1007/s00439-004-1167-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1167-x

Keywords

Search

Navigation