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.


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). "
    [Show abstract] [Hide abstract] ABSTRACT: The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.
    Full-text · Article · Aug 2013 · Frontiers in Cellular Neuroscience
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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). "
    [Show abstract] [Hide abstract] ABSTRACT: Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.
    Full-text · Article · Jul 2013
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    • "CIMA-1 is a member of the solute carrier SLC17 family that includes sialin. Although sialin is capable of transporting a variety of cargos depending on its biological context (Miyaji et al., 2010Miyaji et al., , 2011 Qin et al., 2012), its role as a lysosomal transporter of acidic monosaccharides has been implicated in neurological diseases (Verheijen et al., 1999; Wreden et al., 2005). Importantly, several studies suggest that sialin regulates intercellular adhesion via the modulation of glycoconjugate export from the lysosome (Galuska et al., 2010; Hildebrandt et al., 2009; Morin et al., 2004; Myall et al., 2007; Prolo et al., 2009). "
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