Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases

Abstract

Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland1,2 (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases3. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid5 is impaired in lysosomal membranes from Salla and ISSD patients6. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14–q15 in a linkage study using Finnish families7,8. Salla disease and ISSD were further shown to be allelic disorders9. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene10. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Amino acid sequence and hydrophobicity plot of human sialin.
Figure 2: Expression of SLC17A5 mRNA in various human tissues.
Figure 3: The R39C mutation and its segregation in a Finnish family from the Salla area as shown by an allele-specific PCR assay.
Figure 4: Putative two-dimensional model of human sialin.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Aula, P. et al. 'Salla disease': a new lysosomal storage disorder. Arch. Neurol. 36, 88–94 (1979).

    Article  CAS  Google Scholar 

  2. Gahl, W.A., Schneider, J.A. & Aula, P.P. Lysosomal transport disorders: cystinosis and sialic acid storage disorders. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 3763–3797 (McGraw-Hill, New York, 1995).

    Google Scholar 

  3. Stevenson, R.E. et al. Sialic acid storage disease with sialuria: clinical and biochemical features in the severe infantile type. Pediatrics 72, 441–449 (1983).

    CAS  PubMed  Google Scholar 

  4. Haataja, L. et al. Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder. Neuropediatrics. 25, 1–7 (1994).

    Article  Google Scholar 

  5. Mancini, G.M.S., de Jonge, H.R., Galjaard, H. & Verheijen, F.W. Characterization of a proton-driven carrier for sialic acid in the lysosomal membrane. Evidence for a group-specific transport system for acidic monosaccharides. J. Biol. Chem. 264, 15247–15254 (1989).

    CAS  PubMed  Google Scholar 

  6. Mancini, G.M.S., Beerens, C.E.M.T., Aula, P.P. & Verheijen, F.W. Sialic acid storage diseases: a multiple lysosomal transport defect for acidic monosaccharides. J. Clin. Invest. 87, 1329–1335 (1991).

    Article  CAS  Google Scholar 

  7. Haataja, L. et al. The genetic locus for free sialic acid storage disease maps to the long arm of chromosome 6. Am. J. Hum. Genet. 54, 1042–1049 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Schleutker, J. et al. Linkage disequilibrium utilized to establish a refined genetic position of the Salla disease locus on 6q14–q15. Genomics 27, 286–292 (1995).

    Article  CAS  Google Scholar 

  9. Schleutker, J. et al. Lysosomal free sialic acid storage disorders with different phenotypic presentations—infantile-form sialic acid storage disease and Salla disease—represent allelic disorders on 6q14–15. Am. J. Hum. Genet. 57, 893–901 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Leppanen, P., Isosomppi, J., Schleutker, J., Aula, P. & Peltonen, L. A physical map of the 6q14–q15 region harboring the locus for the lysosomal membrane sialic acid transport defect. Genomics 37, 62–67 (1996).

    Article  CAS  Google Scholar 

  11. Deloukas, P. et al. A physical map of 30,000 human genes. Science 282, 744–746 (1998).

    Article  CAS  Google Scholar 

  12. Boguski, M.S., Lowe, T.M.J. & Tolstoshev, C.M. dbEST—database for "expressed sequence tags". Nature Genet. 4, 332–333 (1993).

    Article  CAS  Google Scholar 

  13. Lennon, G., Auffray, C., Polymeropoulos, M. & Soares, M.B. The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics 33, 151–152 (1996).

    Article  CAS  Google Scholar 

  14. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  15. Mancini, G.M.S., Beerens, C.E.M.T., Galjaard, H. & Verheijen, F.W. Functional reconstitution of the lysosomal sialic acid carrier into proteoliposomes. Proc. Natl Acad Sci. USA 89, 6609–6613 (1992).

    Article  CAS  Google Scholar 

  16. Havelaar, A.C., Mancini, G.M.S., Beerens, C.E.M.T., Souren, R.M.A. & Verheijen, F.W. Purification of the lysosomal sialic acid transporter: functional characteristics of a monocarboxylate transporter. J. Biol. Chem. 273, 34568–34574 (1998).

    Article  CAS  Google Scholar 

  17. Havelaar, A.C., Beerens, C.E.M.T., Mancini, G.M.S. & Verheijen, F.W. Transport of organic anions by the lysosomal sialic acid transporter: a functional approach towards the gene for sialic acid storage disease. FEBS Lett. 446, 65–68 (1999).

    Article  CAS  Google Scholar 

  18. Pao, S.S., Paulsen, I.T. & Saier, M.H. Jr Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62, 1–34 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ni, B. et al. Molecular cloning, expression, and chromosomal localization of a human brain-specific Na+-dependent inorganic phosphate cotransporter. J. Neurochem. 66, 2227–2238 (1996).

    Article  CAS  Google Scholar 

  20. Chong, S.S., Kristjansson, K., Zoghbi, H.Y. & Hughes, M.R. Molecular cloning of the cDNA encoding a human renal sodium phosphate transport protein and its assignment to chromosome 6p21.3–p23. Genomics 18, 355–359 (1993).

    Article  CAS  Google Scholar 

  21. Wu, D.Y., Ugozzoli, L., Pal, B.K. & Wallace, R.B. Allele-specific enzymatic amplification of β-globin genomic DNA for diagnosis of sickle cell anemia. Proc. Natl Acad. Sci. USA 86, 2757–2760 (1989).

    Article  CAS  Google Scholar 

  22. Peltonen, L. Molecular background of the Finnish disease heritage. Ann. Med. 29, 553–556 (1997).

    Article  CAS  Google Scholar 

  23. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

  24. Thompson, J.D., Higgins, D.G. & Gibson,T.J. 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 (1994).

    Article  CAS  Google Scholar 

  25. Claros, M.G. & von Heijne, G. TopPred II: an improved software for membrane protein structure predictions. Comput. Appl. Biosci. 6, 685–686 (1994).

    Google Scholar 

  26. Schleutker, J., Sistonen, P. & Aula, P. Haplotype analysis in prenatal diagnosis and carrier identification of Salla disease. J. Med. Genet. 33, 36–41 (1996).

    Article  CAS  Google Scholar 

  27. Tondeur, M. et al. Infantile form of sialic acid storage disorder: clinical, ultrastructural, and biochemical studies in two siblings. Eur. J. Pediatr. 139, 142–147 (1982).

    Article  CAS  Google Scholar 

  28. Berra, B. et al. Infantile sialic acid storage disease: biochemical studies. Am. J. Med. Genet. 58, 24–31 (1995).

    Article  CAS  Google Scholar 

  29. Lemyre, E. et al. Clinical spectrum of infantile free sialic acid storage disease. Am. J. Med. Genet. 82, 385–391 (1999).

    Article  CAS  Google Scholar 

  30. Cameron, P.D., Dubowitz, V., Besley, G.T. & Fensom, A.H. Sialic acid storage disease. Arch. Dis. Child. 65, 314–315 (1990).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients and families for contributing to this project; B. Bembi, M. Lambert, M. Potier, E. Vamos, F. van Hoof and A.H. Fensom for providing patient cell lines; B. Oostra for helpful suggestions; and T. de Vries-Lentsch for photographic work. This study was supported by the Stichting Klinische Genetica Rotterdam, the Dutch research foundation, the Academy of Finland and the Hjelt Fund of the Pediatric Research Foundation, Finland.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Frans W. Verheijen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verheijen, F., Verbeek, E., Aula, N. et al. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet 23, 462–465 (1999). https://doi.org/10.1038/70585

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/70585

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing