Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin

Aula, Nina; Jalanko, Anu; Aula, Pertti; Peltonen, Leena

doi:10.1016/s1096-7192(02)00124-5

Cited by 32 publications

(23 citation statements)

References 23 publications

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“…The G409E mutation alters the localization of sialin Previous studies have suggested that mislocalization of disease-associated mutant sialin can lead to the loss of sialic acid transport activity in lysosomes, the presumed site of function [4,5,8]. Although sialin has been described as a lysosomal protein [4,9], our attempts to find another protein that consistently colocalizes with sialin have been unsuccessful.…”

Section: Resultsmentioning

confidence: 95%

G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking

Myall

Wreden

Wlizla

et al. 2007

Molecular Genetics and Metabolism

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Two disease-associated missense mutations in the sialin gene (G328E and G409E) have recently been identified in patients with lysosomal free sialic acid storage disease. We have assessed the effect of these mutations and find complete loss of measurable transport activity with both and impaired trafficking of the G409E protein. These results suggest that the two residues are important for proper function of sialin and confirm the association of loss of transport with disease causative mutations.

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Section: Resultsmentioning

confidence: 95%

G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking

Myall

Wreden

Wlizla

et al. 2007

Molecular Genetics and Metabolism

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“…SLC17A5 (which encodes sialin) was expressed at high levels in both types of salivary glands (Table S1). Sialin functions as a lysosomal SA/H + transporter involved in SA efflux, although it is detected in the plasma membrane of neurons (18,19) where it mediates aspartate and glutamate transport. The protein is widely expressed in such tissues as brain, heart, lung, liver, kidney, and mouse submandibular glands (20)(21)(22).…”

Section: Involvement Of Sialin In 2nomentioning

confidence: 99%

“…The protein is widely expressed in such tissues as brain, heart, lung, liver, kidney, and mouse submandibular glands (20)(21)(22). Importantly, mutations in sialin are causative factors in the neurodegenerative disorders Salla disease and ISSD (18,23). We validated the expression of sialin in various human tissues by qPCR (Fig.…”

Section: Involvement Of Sialin In 2nomentioning

confidence: 99%

Sialin ( SLC17A5 ) functions as a nitrate transporter in the plasma membrane

Qin

Liu

Sun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

174

142

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In vivo recycling of nitrate (NO 3 − ) and nitrite (NO 2 − ) is an important alternative pathway for the generation of nitric oxide (NO) and maintenance of systemic nitrate–nitrite–NO balance. More than 25% of the circulating NO 3 − is actively removed and secreted by salivary glands. Oral commensal bacteria convert salivary NO 3 − to NO 2 − , which enters circulation and leads to NO generation. The transporters for NO 3 − in salivary glands have not yet been identified. Here we report that sialin ( SLC17A 5 ), mutations in which cause Salla disease and infantile sialic acid storage disorder (ISSD), functions as an electrogenic 2NO 3 − /H + cotransporter in the plasma membrane of salivary gland acinar cells. We have identified an extracellular pH-dependent anion current that is carried by NO 3 − or sialic acid (SA), but not by Br − , and is accompanied by intracellular acidification. Both responses were reduced by knockdown of sialin expression and increased by the plasma membrane-targeted sialin mutant (L22A-L23A). Fibroblasts from patients with ISSD displayed reduced SA- and NO 3 − -induced currents compared with healthy controls. Furthermore, expression of disease-associated sialin mutants in fibroblasts and salivary gland cells suppressed the H + -dependent NO 3 − conductance. Importantly, adenovirus-dependent expression of the sialinH183R mutant in vivo in pig salivary glands decreased NO 3 − secretion in saliva after intake of a NO 3 − -rich diet. Taken together, these data demonstrate that sialin mediates nitrate influx into salivary gland and other cell types. We suggest that the 2NO 3 − /H + transport function of sialin in salivary glands can contribute significantly to clearance of serum nitrate, as well as nitrate recycling and physiological nitrite-NO homeostasis.

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“…The G371V Mutation Leads to Retention of Sialin in the ER-In a previous report in which the localization of sialin was compared with LAMP1, a lysosomal/late endosomal marker, recombinant proteins with the Salla mutation and the short deletion were found to be mislocalized, leading the authors to suggest that improper targeting could contribute to the defect associated with these mutations (29). In trying to determine the extent to which other mutations influence trafficking of sialin we found that wild-type sialin only partially localizes with LAMP1 and LAMP2 in HeLa cells (data not shown), suggesting that colocalization studies with these endogenous antigens would be difficult.…”

Section: Disruption Of Putative Adaptor Protein-binding Domain Leads mentioning

confidence: 99%

Varied Mechanisms Underlie the Free Sialic Acid Storage Disorders

Wreden¹,

Wlizla²,

Reimer

2005

Journal of Biological Chemistry

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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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Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin

Cited by 32 publications

References 23 publications

G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking

G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking

Sialin ( SLC17A5 ) functions as a nitrate transporter in the plasma membrane

Varied Mechanisms Underlie the Free Sialic Acid Storage Disorders

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