Disease relevance of SLC17A5

• Salla disease, one of three disease phenotypes that manifest increased urinary excretion of unconjugated sialic acid, is an autosomal recessive condition caused by a mutation in SLC17A5 [1].
• When the two ratios (ratio of cancer to normal HLBP31 mRNA and ratio of cancer to normal 67 LR mRNA) were compared, HLBP31 mRNA/67 LR mRNA was significantly lower (P less than .05) in primary tumors with metastases (mean +/- SD, 0.3 +/- 0.2) than in primary cancers without metastases (mean +/- SD, 0.7 +/- 0.5) [2].
• On average, the level of HLBP31 mRNA was decreased 50% +/- 30% (+/- SD) in the colon cancers [2].
• 0. However, there was a statistically significant correlation between the AST/ALT ratio and the presence of cirrhosis [3].
• We analyzed the AST/ALT ratio in 177 patients with various forms of nonalcoholic chronic liver disease who underwent medical evaluation and percutaneous liver biopsy [3].

Psychiatry related information on SLC17A5

• 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 [4].
• Absolute sensation threshold (AST), pain threshold (PTh), and pain tolerance (PTo) to tooth pulp shock were measured in microamperes during administration of each of 3 concentrations of N2O (15%, 30%, and 45%, with oxygen) [5].
• Nine subjects underwent two counterbalanced 36-hour trials involving sleep deprivation (SD) and no sleep deprivation (NSD) [6].
• It is concluded that changes in the NSD parameters reflect (1) the depressing effect of both alcohol and the test situation, which was more or less evident in most subjects, and (2) the individual degree of and type of CNS reaction to alcohol consumption [7].
• In a sensitivity analysis, there was no correlation between AST/ALT ratio and disease stage for patients with a history of alcohol abuse [8].

High impact information on SLC17A5

• Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases [9].
• 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 [9].
• A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients [9].
• Cell loss was greatest among CD19+ sIg- B cell progenitors (mean cell recovery +/- SD = 7.2 +/- 11.7% of recovery in control cultures) and extended to CD19+CD34+ B cells (the most immature subset; 7.6 +/- 2.2%) [10].
• Human CobINA was found to be a glycoprotein containing at least 10.7% carbohydrate and to have a normal serum concentration of 34 +/- 7 mug/ml (mean +/- 1 SD) [11].

Chemical compound and disease context of SLC17A5

• Several mutations of the sialin gene, SLC17A5, are known, leading either to the severe neonatal/infantile disease or to the milder, adult-type developmental disorder, Salla disease [12].
• The ratio of the serum aspartate to alanine amino-transferase levels (AST/ALT) is often used as a clue to the etiology of the underlying liver disease [3].
• In co-infected patients, ALT increase (> or = 1.25 of normal), but not AST increase, at the time of indinavir initiation was statistically related to the occurrence of nephrolithiasis [13].
• RESULTS: COMS patients were screened annually for metastasis and new cancers using LFTs (alkaline phosphatase, AST, ALT, or bilirubin) [14].
• No association was found between the serum AST (aspartate aminotransferase), activity grade, or stage of liver disease and the presence of occult hepatitis B [15].

Biological context of SLC17A5

• A novel mutation in the SLC17A5 gene causing both severe and mild phenotypes of free sialic acid storage disease in one inbred Bedouin kindred [16].
• Electron microscopy of a skin biopsy showed lysosomal enlargement with oligosaccharide storage, and confirmatory molecular genetic testing revealed compound heterozygosity for two new SLC17A5 mutations [17].
• The first studies were based on the sialic acid assays alone, but the location of the gene enabled the use of genetic linkage analysis and, more recently, the identification of the SLC17A5 gene and disease-causing mutations added yet another possibility for prenatal studies [18].
• Interestingly, while two missense mutations and one small, in-frame deletion associated with ISSD abolished transport, the mutation causing Salla disease (R39C) slowed down, but did not stop, the transport cycle, thus explaining why the latter disorder is less severe [19].
• Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes [20].

Anatomical context of SLC17A5

• Lysosomal free sialic acid storage diseases are recessively inherited allelic neurodegenerative disorders that include Salla disease (SD) and infantile sialic acid storage disease (ISSD) caused by mutations in the SLC17A5 gene encoding for a lysosomal membrane protein, sialin, transporting sialic acid from lysosomes [21].
• Prenatal diagnosis of SASD is possible either by determination of free sialic acid concentration or by mutation analysis of the SLC17A5 gene in fetal specimen, in chorionic villus biopsy particularly [12].
• To develop a functional assay of human sialin, we redirected the protein to the plasma membrane by mutating a dileucine-based internalization motif [19].
• 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 [22].
• Here we analyzed sialin in mouse central nervous system (CNS) and primary cortical and hippocampal neurons and glia [23].

Associations of SLC17A5 with chemical compounds

• 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 [4].
• Molecular studies showed that all four affected individuals were homozygous for the same novel 983G > A mutation in exon 8 of the SLC17A5 gene, replacing glycine with glutamic acid at position 328 of the sialin protein [16].
• This region contained 55 genes, including SLC17A5, the gene encoding the lysosomal N-acetylneuraminic acid transport protein [24].
• About 20 systems for transporting small molecules across the lysosomal membrane have been characterized but only two proteins, cystinosin and sialin, involved in the transport of cystine and sialic acid, respectively, have been cloned [25].
• The addition of iron supplementation to ethanol resulted in a further twofold increment in mean MDA, 4HNE, ALT, and AST [26].

Analytical, diagnostic and therapeutic context of SLC17A5

• The TDH result was 41.6 +/- 31.7% (SD) in a group of chronic pancreatitis patients (n = 22) and 91.5 +/- 4.8% in the control group (n = 47) [27].
• Patients who developed hypernatremia during hospitalization were younger than patients who developed hypernatremia before hospital admission (mean age +/- SD, 58.9 +/- 19.2 years compared with 76.6 +/- 16.6 years; P < 0.01) but did not differ in age from the patients of the general hospitalized population [28].
• At diagnosis, 67 patients (42%) had raised aspartate and/or alanine transaminase levels (AST and ALT; mean, 47 IU/L, range, 30 to 190; and 61 IU/L, range, 25 to 470, respectively), whereas 91 patients had normal liver function tests (LFT) [29].
• The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively [30].
• To answer this question we compared the histopathological diagnoses in 170 biopsy specimens from 70 adult transplant recipients obtained during the first 180 days, with the concentrations of the serum bilirubin and the activities of AST, ALT and alkaline phosphatase measured at the same time [31].

References