Varied Mechanisms Underlie the Free Sialic Acid Storage Disorders

Stanford University, Palo Alto, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2005; 280(2):1408-16. DOI: 10.1074/jbc.M411295200
Source: PubMed


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.

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Available from: Marcin Wlizla, Feb 04, 2016
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    • "Several studies implied a direct correlation between the activity of sialin transport and the severity of the disease phenotype . Mutant forms of sialins in persons suffering from ISSD show complete absence of H + /sialic co-transport activity, whereas the mutant forms of sialins found in Salla disease patients still exhibit 20–60% of normal H + /sialic co-transport (Morin et al., 2004; Wreden et al., 2005; Myall et al., 2007; Ruivo et al., 2008). Salla disease and ISSD disorders predominantly affect the CNS, eliciting varying degrees of developmental delay in motor and cognitive skills, epilepsy, and premature death and are marked by cytoplasmatic vacuoles and hypomyelination (Prolo et al., 2009). "
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    • "bearing some residual transporter activity in vitro (Aula et al. 2000; Morin et al. 2004; Verheijen et al. 1999; Wreden et al. 2005; Mochel et al. 2009). In contrast, a wide range of mutation types are seen in ISSD; those studied in vitro appear to be functionally null (Aula et al. 2000; Morin et al. 2004; Myall et al. 2007; Ruivo et al. 2008; Wreden et al. 2005). Previous reports have described SLC17A5 mutations in Finnish, Swedish, Danish, Italian, French, Polish, Yugoslav, Turkish, Bedouin, Japanese, and North American (including French Canadian) patients (Biancheri et al. 2002, 2005; Coker et al. 2009; Erikson et al. 2002; Landau et al. 2004; Nakano et al. 1996; Sonderby Christensen et al. 2003; Tylki-Szymanska et al. 2003; Verheijen et al. 1999). "
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    Full-text · Article · Jul 2013
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    • "Recently, a screen for synaptic mutants in Drosophila uncovered fuseless (fusl), the putative homologue of the mammalian Sialin 8-pass transmembrane sialic acid transporter (Long et al., 2008). In vertebrates, the monosaccharide sialic acid cleaved from sialoglycoconjugates is exported across membranes by the Sialin transporter (Morin et al., 2004) (Wreden et al., 2005), and two inherited cognitive dysfunction disease occur in humans when the sialin gene is mutant (Verheijen et al., 1999). At the Drosophila NMJ, fusl mutants display >75% reduction in evoked synaptic transmission due to a presynaptic requirement in localizing Cacophony Ca 2+ channels (Kawasaki et al., 2000; Xing et al., 2005). "
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