Functional characterization of wild-type and mutant human sialin

EMBO J. 2004 Nov 24;23(23):4560-70. doi: 10.1038/sj.emboj.7600464. Epub 2004 Oct 28.


The modification of cell surface lipids or proteins with sialic acid is essential for many biological processes and several diseases are caused by defective sialic acid metabolism. Sialic acids cleaved off from degraded sialoglycoconjugates are exported from lysosomes by a membrane transporter, named sialin, which is defective in two allelic inherited diseases: infantile sialic acid storage disease (ISSD) and Salla disease. To develop a functional assay of human sialin, we redirected the protein to the plasma membrane by mutating a dileucine-based internalization motif. Cells expressing the plasmalemmal construct accumulated neuraminic acid at acidic pH by a process equivalent to lysosomal efflux. The assay was used to determine how pathogenic mutations affect transport. Interestingly, while two missense mutations and one small, in-frame deletion associated with ISSD abolished transport, the mutation causing Salla disease (R39C) slowed down, but did not stop, the transport cycle, thus explaining why the latter disorder is less severe. Since neurological symptoms predominate in Salla disease, our results suggest that sialin is rate-limiting to specific sialic acid-dependent processes of the nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Cell Line
  • Cell Membrane / metabolism
  • Cloning, Molecular
  • Endocytosis
  • Humans
  • Hydrogen-Ion Concentration
  • Mutation
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism*
  • Protein Transport
  • Sialic Acid Storage Disease / genetics
  • Sialic Acids / metabolism
  • Symporters / genetics
  • Symporters / metabolism*


  • Organic Anion Transporters
  • Sialic Acids
  • Symporters
  • sialic acid transport proteins