Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased amounts of free sialic acid were found in cultured fibroblasts and urine of a 4-year-7-month-old Italian boy with mental retardation, hypotonia, failure to thrive, coarse facial features, convergent strabismus, pale skin and fair hair. Ultramicroscopic examination of conjunctival and skin tissues showed a number of membrane-bound vacuoles containing low-density granular material in the cytoplasm of the fibroblasts. The clinical, biochemical and ultrastructural findings are similar to those described in Salla disease. Neuraminidase activity is normal. The molecular basis of the sialic acid storage disease is not known. Evidence for defective transport of sialic acid across the lysosomal membrane has been demonstrated in the patient's fibroblasts. It is possible that this might represent the metabolic abnormality.
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PMID:Free sialic acid storage disease. A new Italian case. 356 61

Salla disease is a lysosomal storage disorder characterized by mental retardation and disturbed sialic acid metabolism. To study endogenous synthesis and breakdown of sialic acid, fibroblasts were incubated for 5 d in the presence and then in the absence of N-[3H]acetylmannosamine. Labeling of free sialic acid was 5-10 times higher in mutant than in normal cells. Radioactivity decreased in 4 d by 75% in normal but only by 30% in mutant fibroblasts. The labeling pattern was not normalized upon coculture of mutant and normal cells. To study the metabolism of extracellular sialic acid, low-density lipoprotein (LDL) was labeled in the sialic acid moiety (periodate-NaB3H4) or in the protein moiety (125I). Binding, internalization, lysosomal degradation, and exit of products of protein catabolism were similar in normal and mutant fibroblasts. Upon incubation with LDL labeled in the sialic acid moiety, mutant cells accumulated 2-3 times more free sialic acid radioactivity than normal fibroblasts, mostly in the lysosomal fraction. After a 24-h chase incubation, radioactivity in free sialic acid decreased by 70-80% in normal but only by 10-30% in mutant cells. In mutant fibroblasts, 40% of the radioactivity remained in lysosomes, whereas no labeled free sialic acid was detected in lysosomes from normal fibroblasts. We conclude that in Salla disease, fibroblast endogenous synthesis of sialic acid and lysosomal cleavage of exogenous glycoconjugates is normal, but free sialic acid cannot leave the lysosome. These findings suggest that the basic defect in Salla disease is deficient transport of free sialic acid through the lysosomal membrane.
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PMID:Studies on the defect underlying the lysosomal storage of sialic acid in Salla disease. Lysosomal accumulation of sialic acid formed from N-acetyl-mannosamine or derived from low density lipoprotein in cultured mutant fibroblasts. 394 69

Increased amounts of free sialic acid were found in body fluids, leukocytes, cultured fibroblasts, and liver tissue of a four-year-old boy with mental retardation, ataxia, and clinical and radiologic findings of a mild mucopolysaccharidosis. A diagnosis of Salla disease was made though in contrast to earlier reports, recurrent upper respiratory infections and hepatosplenomegaly were present already in infancy, and skeletal abnormalities of dysostosis multiplex were found in early childhood. Free sialic acid in the urine was identified as N-acetylneuraminic acid by 1H-NMR spectroscopy. Sialidase activities were normal. Increased amounts of bound sialic acid were found in liver and cultured fibroblasts and were attributed to an intracellular inhibition of sialyloligosaccharide-degrading neuraminidase by excessive amounts of free neuraminic acid. The molecular basis of N-acetylneuraminic acid storage disease is unknown but may be related to a defective transport mechanism preventing neuraminic acid from leaving the lysosomal compartment.
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PMID:N-Acetylneuraminic acid storage disease. 404 64

Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.
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PMID:A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. 1058 Oct 36

Salla disease (SD) and infantile sialic acid storage disease (ISSD) are recessively inherited, neuro-degenerative disorders caused by mutations in the SLC17A5 gene. The gene product, sialin, is a lysosomal membrane protein which transports free sialic acid across the membrane. Although the function of sialin is basically known, the details of biosynthesis and intracellular trafficking as well as functional consequences of disease mutations in the SLC17A5 gene are not characterized. Here we studied for the first time the expression, localization, and targeting of the wild-type sialin as well as two mutant polypeptides; one mimicking the Finnish founder mutation, R39C (Salla(FIN)), and the other a deletion (del268-272) found in ISSD patients using in vitro expression of the corresponding cDNA constructs. The wild-type sialin was targeted to lysosomes whereas a significant fraction of the Salla(FIN) polypeptides and the majority of the ISSD polypeptides remained in the Golgi compartment. Further, using a temperature block of intracellular transport, we observed that the rate of the trafficking of the mutant polypeptides to lysosomes is significantly slower than that of their wild-type counterpart. These findings are in line with the phenotypic differences between SD and ISSD, the former presenting mental retardation with long life span in contrast to the latter being an early fatal disorder.
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PMID:Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin. 1517 96