RGD Reference Report - Varied mechanisms underlie the free sialic acid storage disorders. - Rat Genome Database

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Varied mechanisms underlie the free sialic acid storage disorders.

Authors: Wreden, CC  Wlizla, M  Reimer, RJ 
Citation: Wreden CC, etal., J Biol Chem. 2005 Jan 14;280(2):1408-16. Epub 2004 Oct 29.
RGD ID: 1624225
Pubmed: (View Article at PubMed) PMID:15516337
DOI: Full-text: DOI:10.1074/jbc.M411295200

Salla disease and infantile sialic acid storage disorder are autosomal recessive neurodegenerative diseases characterized by loss of a lysosomal sialic acid transport activity and the resultant accumulation of free sialic acid in lysosomes. Genetic analysis of these diseases has identified several unique mutations in a single gene encoding a protein designated sialin (Verheijen, F. W., Verbeek, E., Aula, N., Beerens, C. E., Havelaar, A. C., Joosse, M., Peltonen, L., Aula, P., Galjaard, H., van der Spek, P. J., and Mancini, G. M. (1999) Nat. Genet. 23, 462-465; Aula, N., Salomaki, P., Timonen, R., Verheijen, F., Mancini, G., Mansson, J. E., Aula, P., and Peltonen, L. (2000) Am. J. Hum. Genet. 67, 832-840). From the biochemical phenotype of the diseases and the predicted polytopic structure of the protein, it has been suggested that sialin functions as a lysosomal sialic acid transporter. Here we directly demonstrate that this activity is mediated by sialin and that the recombinant protein has functional characteristics similar to the native lysosomal sialic acid transport system. Furthermore, we describe the effect of disease-causing mutations on the protein. We find that the majority of the mutations are associated with a complete loss of activity, while the mutations associated with the milder forms of the disease lead to reduced, but residual, function. Thus, there is a direct correlation between sialin function and the disease state. In addition, we find with one mutation that the protein is retained in the endoplasmic reticulum, indicating that altered trafficking of sialin is also associated with disease. This analysis of the molecular mechanism of sialic acid storage disorders is a further step in identifying therapeutic approaches to these diseases.

Annotation

Gene Ontology Annotations    

Biological Process

Cellular Component
lysosome  (IDA)

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Slc17a5  (solute carrier family 17 member 5)


Additional Information