Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides.

Mancini, Grazia M.S.; Beerens, Cecile; Aula, Pertti; Verheijen, Frans W.

doi:10.1172/jci115136

Cited by 63 publications

(44 citation statements)

References 39 publications

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“…Compared with ISSD, Salla disease is clinically less severe and is associated with lower levels of free sialic acid in both urine and cells cultured from patients. An unresolved issue has been the difference in phenotypes for Salla disease and ISSD, despite a complete absence of measurable sialic acid transport activity in lysosomes derived from patients with both diseases (15,16,27). Although this has been attributed to a lack of sensitivity in the methods used to measure lysosmal transport activity, some uncertainty has persisted.…”

Section: Discussionmentioning

confidence: 99%

“…Although a partial reduction in transport activity could lead to disease, the absence of a phenotype in heterozygote carriers of the free sialic acid storage disorders, who have approximately half the normal lysosomal sialic acid transport activity (27), suggests that activity would need to be reduced by more than 50%. Therefore, we wanted to know, more precisely, the effect of the R39C and K136E mutations on activity.…”

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

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…The two main clinical phenotypes are Salla or adult-type disease presenting with mental retardation, ataxia, and normal life span and ISSD with early-onset psychomotor retardation, coarse facies, hepatosplenomegaly and death early in childhood. Both disorders are probably a gradation of the same defect that appears to involve impairment of an active proton-driven and substrate-specific transport system of free sialic acid across the lysosomal membrane [Mancini et al, 1989[Mancini et al, , 1991Tietze et al, 1989]. The end result is an accumulation of free sialic acid within the lysosome.…”

Section: Introductionmentioning

confidence: 99%

Clinical spectrum of infantile free sialic acid storage disease

et al. 1999

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Infantile free sialic acid storage disease (ISSD) is a rare autosomal recessive metabolic disorder caused by a lysosomal membrane transport defect, resulting in accumulation of free sialic acid within lysosomes. Only a few cases have been described. We report on three new cases of ISSD with different modes of presentation: an infant with nephrotic syndrome, a case of fetal and neonatal ascites with heart failure, and a case of fetal ascites with esophageal atresia type III. From these patients and a review of the literature (27 cases total) we draw the following conclusions. 1) ''Coarse facies,'' fair complexion, hepatosplenomegaly, and severe psychomotor retardation are constant findings in this disorder. 2) Nephrotic syndrome occurred in most cases (four in seven) in which renal evaluation was performed. Therefore, ISSD is an important cause of nephrosis in infants with a storage disorder phenotype. 3) Fetal/neonatal ascites or hydrops was the mode of presentation in 13 (60%) of 21 cases. Thus, ISSD enters in the differential diagnosis of hydrops fetalis with a storage disease phenotype. 4) Cardiomegaly was evident in nine cases. 5) Corneae were always clear, and albinoid fundi were reported in five cases. 6) Dysostosis multiplex was not prominent. 7) Bone marrow aspiration could be negative. 8) Death ensued in early infancy with a mean age of 13.1 months. All reported deaths were caused by respiratory infections. Am. J. Med. Genet. 82:385-391, 1999.

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“…In ISSD and Salla disease, a defect in sialin activity has been shown (Mancini et al 1991). So, a large amount of free sialic acid residues must be accumulated in lysosomes, and this might secondarily cause a defect in the catalytic metabolism of sialyl glycoconjugates in lysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…They are caused by impaired anion transport across the lysosomal membrane (Mancini et al 1991), and the responsible gene has been identified as the SLC17A5-gene (Verheijen et al 1999;Aula et al 2000) located on the long arm of chromosome 6.…”

Section: Introductionmentioning

confidence: 99%

Clinical, biochemical, and cytochemical studies on a Japanese Salla disease case associated with a renal disorder

et al. 2004

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We report the first Japanese case of Salla disease. A 5-year-old male patient developed unique proteinuria with other clinical manifestations, including coarse facies, dysostosis multiplex, mild mitral valve regurgitation, umbilical and inguinal herniation, and mild developmental delay. Pathological analysis of biopsied kidney tissues showed marked vacuolation of podocytes, mesangial cells, capillary endothelial cells, and tubular cells. Biochemical studies involving thinlayer chromatography and mass spectrometry revealed increased excretion of free sialic acid (N-acetylneuraminic acid) into the patient's urine. Immuno-and lectin staining of the patient's cells demonstrated the accumulation of sialyl and asialyl glycoconjugates in lysosomes and late endosomes. A defect in sialyl glycoconjugate metabolism is thought to have occurred in the patient's cells, besides impairment of the lysosomal transport of free sialic acid residues. A renal disorder should be considered as an important manifestation, not only in infantile free sialic acid storage disease but also in Salla disease.

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Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides.

Cited by 63 publications

References 39 publications

Varied Mechanisms Underlie the Free Sialic Acid Storage Disorders

Varied Mechanisms Underlie the Free Sialic Acid Storage Disorders

Clinical spectrum of infantile free sialic acid storage disease

Clinical, biochemical, and cytochemical studies on a Japanese Salla disease case associated with a renal disorder

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