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

Nature Genetics volume 23, pages 462–465 (1999)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Department of Clinical Genetics, Erasmus University and Academic Hospital, Erasmus Medical Centre of Rotterdam, Rotterdam, The Netherlands

    Frans W. Verheijen, Elly Verbeek, Cecile E.M.T. Beerens, Adrie C. Havelaar, Marijke Joosse, Hans Galjaard & Grazia M.S. Mancini

  2. Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland

    Nina Aula & Leena Peltonen

  3. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Pertti Aula

  4. Akzo-Nobel/N.V.Organon, Oss, The Netherlands

    Peter J. van der Spek

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  1. Frans W. Verheijen
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Correspondence to Frans W. Verheijen.

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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

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