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American Journal of Human Genetics Jun 1999Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic acid (NeuAc, sialic...
Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic acid (NeuAc, sialic acid). Overproduction of NeuAc is believed to result from loss of feedback inhibition of uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). We report the cloning and characterization of human UDP-GlcNAc 2-epimerase cDNA, with mutation analysis of three patients with sialuria. Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266. The heterozygous nature of the mutant allele in all three patients reveals a dominant mechanism of inheritance for sialuria.
Topics: Allosteric Site; Amino Acid Sequence; Base Sequence; Carbohydrate Epimerases; Carrier Proteins; Child, Preschool; DNA, Complementary; Female; Humans; Male; Metabolism, Inborn Errors; Molecular Sequence Data; Mutation; N-Acetylneuraminic Acid
PubMed: 10330343
DOI: 10.1086/302411 -
FEBS Letters Mar 1999Transport of sialic acid through the lysosomal membrane is defective in the human sialic acid storage disease. The mammalian sialic acid carrier has a wide substrate...
Transport of sialic acid through the lysosomal membrane is defective in the human sialic acid storage disease. The mammalian sialic acid carrier has a wide substrate specificity for acidic monosaccharides. Recently, we showed that also non-sugar monocarboxylates like L-lactate are substrates for the carrier. Here we report that other organic anions, which are substrates for carriers belonging to several anion transporter families, are recognized by the sialic acid transporter. Hence, the mammalian system reveals once more novel aspects of solute transport, including sugars and a wide array of non-sugar compounds, apparently unique to this system. These data suggest that the search for the sialic acid storage disease gene can be initiated by a functional selection of genes from a limited number of anion transporter families. Among these, candidates will be identified by mapping to the known sialic acid storage disease locus.
Topics: Animals; Anions; Biological Transport; Carrier Proteins; Humans; Liver; Lysosomal Storage Diseases; Lysosomes; Membrane Proteins; N-Acetylneuraminic Acid; Nucleotide Transport Proteins; Rats; Substrate Specificity
PubMed: 10100616
DOI: 10.1016/s0014-5793(99)00187-8 -
Journal of Nuclear Medicine : Official... Jan 1999Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed...
UNLABELLED
Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelination, but the biological mechanism of the brain dysfunction is unknown.
METHODS
Nine patients with Salla disease (age 2.5 mo-42 y) presenting the disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-D-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGlc) in individual brain regions were compared with controls.
RESULTS
The FDG PET results showed significantly increased LCMRGlc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum.
CONCLUSION
The increased cerebral glucose utilization is a constant finding in Salla disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms.
Topics: Adolescent; Adult; Brain; Child; Child, Preschool; Fluorodeoxyglucose F18; Glucose; Humans; Infant; Lysosomal Storage Diseases; Magnetic Resonance Imaging; Radiopharmaceuticals; Sialic Acids; Tomography, Emission-Computed
PubMed: 9935050
DOI: No ID Found -
The Journal of Biological Chemistry Dec 1998Sialic acid and glucuronic acid are monocarboxylated monosaccharides, which are normally present in sugar side chains of glycoproteins, glycolipids, and...
Sialic acid and glucuronic acid are monocarboxylated monosaccharides, which are normally present in sugar side chains of glycoproteins, glycolipids, and glycosaminoglycans. After degradation of these compounds in lysosomes, the free monosaccharides are released from the lysosome by a specific membrane transport system. This transport system is deficient in the human hereditary lysosomal sialic acid storage diseases (Salla disease and infantile sialic acid storage disease, OMIM 269920). The lysosomal sialic acid transporter from rat liver has now been purified to apparent homogeneity in a reconstitutively active form by a combination of hydroxyapatite, lectin, and ion exchange chromatography. A 57-kDa protein correlated with transport activity. The transporter recognized structurally different types of acidic monosaccharides, like sialic acid, glucuronic acid, and iduronic acid. Transport of glucuronic acid was inhibited by a number of aliphatic monocarboxylates (i.e. lactate, pyruvate, and valproate), substituted monocarboxylates, and several dicarboxylates. cis-Inhibition, trans-stimulation, and competitive inhibition experiments with radiolabeled glucuronic acid as well as radiolabeled L-lactate demonstrated that L-lactate is transported by the lysosomal sialic acid transporter. L-Lactate transport was proton gradient-dependent, saturable with a Km of 0.4 mM, and mediated by a single mechanism. These data show striking biochemical and structural similarities of the lysosomal sialic acid transporter with the known monocarboxylate transporters of the plasma membrane (MCT1, MCT2, MCT3, and Mev).
Topics: Animals; Biological Transport; Carboxylic Acids; Cell Fractionation; Chromatography; Chromatography, Affinity; Chromatography, Ion Exchange; Durapatite; Humans; Intracellular Membranes; Lectins; Liver; Lysosomal Storage Diseases; Lysosomes; Membrane Transport Proteins; Monosaccharides; Organic Anion Transporters; Plant Lectins; Rats; Rats, Wistar; Substrate Specificity; Symporters
PubMed: 9852127
DOI: 10.1074/jbc.273.51.34568 -
Developmental Medicine and Child... Mar 1997Salla disease is described in two English children. Eighty-seven of the 89 cases so far reported come from Finland. It may be genuinely rare outside Finland or possibly...
Salla disease is described in two English children. Eighty-seven of the 89 cases so far reported come from Finland. It may be genuinely rare outside Finland or possibly underdiagnosed. Although a lysosomal disorder, it lacks many of their more characteristic features. Deterioration, for example, in the paediatric age range is rare. The clinical features are, however, consistent and specific. Definitive diagnosis is achieved by demonstrating increased amounts of free sialic acid in cultured skin fibroblasts. If the colorimetric method in widespread use is employed for this, a false negative result may be obtained. High-pressure liquid chromatography is sufficiently sensitive. It is possible therefore that Salla disease is under-reported, both from lack of clinical awareness and from lack of appropriate laboratory confirmation.
Topics: Child; Child, Preschool; Female; Humans; Lysosomal Storage Diseases; Sialic Acids
PubMed: 9112963
DOI: 10.1111/j.1469-8749.1997.tb07403.x -
The Journal of Biological Chemistry Sep 1996Cultured fibroblasts from normal subjects and from subjects affected by Salla disease, characterized by the lack or misfunction of the membrane carrier responsible for...
Cultured fibroblasts from normal subjects and from subjects affected by Salla disease, characterized by the lack or misfunction of the membrane carrier responsible for the egress of sialic acid from lysosomes, were fed with ganglioside GM3 labeled at the sialic acid acetyl group, [Neu5Ac-3H]GM3, or at C-3 of sphingosine (Sph), [Sph-3H]GM3, or at C-1 of stearoyl chain, [stearoyl-14C]GM3. After a 15-h pulse the total amount of cell-bound GM3 corresponded to about 2% of the endogenous ganglioside content. Cells were then subjected to a 72-h chase, and the radioactive products from both ganglioside catabolism and salvage processes of catabolic fragments were measured. These data indicated that about 50% of the cell-bound ganglioside underwent metabolic processing, suggesting a ganglioside half-life of 2-3 days. [Neu5Ac-3H] formed from [Neu5Ac-3H]GM3 degradation was mostly re-cycled for the biosynthesis of gangliosides and sialoglycoproteins, only a minor part being degraded to [3H]water, which constituted only 1.6% of total metabolite linked radioactivity. [Sph-3H] from the [Sph-3H]GM3 degradation was partly re-cycled for the biosynthesis of gangliosides, neutral glycosphingolipids and sphingomyelin, and partly (about 20% of the total metabolite linked radioactivity) degraded to [3H]water. In Salla fibroblasts metabolic processing of [Neu5Ac-3H]GM3 produced large amounts of free [3H]Neu5Ac, and a reduced incorporation of radioactivity into glycoconjugates (as compared to normal cells). However, the accumulation of free Neu5Ac was not accompanied by an increase of tritiated water. LacCer and Cer from [stearoyl-14C]GM3 catabolism were found to accumulate in Salla fibroblasts, an indication that the enzymes of glycosphingolipid metabolism were affected by the impairment of Neu5Ac egress from lysosomes. Particularly relevant was the accumulation of ceramide which was hardly detectable in control cells.
Topics: Adolescent; Animals; Cattle; Cells, Cultured; Child; DNA; Fibroblasts; G(M3) Ganglioside; Gangliosides; Humans; Lysosomal Storage Diseases; Male; N-Acetylneuraminic Acid; Proteins; Sialic Acids; Sialoglycoproteins; Sphingomyelins
PubMed: 8702969
DOI: 10.1074/jbc.271.36.21738 -
Journal of Medical Genetics Jan 1996Salla disease (SD) is an autosomal recessive disorder in which free sialic acid (N-acetyl neuraminic acid) accumulates in lysosomes. A specific transport mechanism for...
Salla disease (SD) is an autosomal recessive disorder in which free sialic acid (N-acetyl neuraminic acid) accumulates in lysosomes. A specific transport mechanism for acidic monosaccharides on the lysosomal membrane has recently been described, but the molecular deficiency causing SD is still unknown. We have previously mapped the SD gene to 6q14-q15 by means of genetic linkage analysis and restricted the positive chromosomal area to less than 100 kb with linkage disequilibrium mapping. The two best allelic association markers have now retrospectively been used in five prenatal analyses originally studied with sialic acid assays in chorionic villus specimens. In four cases an unaffected fetus was predicted with a probability level of more than 94%, which was in concordance with the biochemical data. One fetus was predicted to be affected with over 96% probability, as was shown by free sialic acid assays in a CVS sample and in fetal tissues after termination of the pregnancy. Risk calculations incorporating disequilibrium were also used to predict the carrier status in members of six families with previous SD cases, and also in a few cases with no known family history of SD. DNA marker based analysis thus provides a reliable method for risk estimations in prenatal cases and for carrier identification of SD.
Topics: Adult; Alleles; Female; Fetal Diseases; Genetic Carrier Screening; Haplotypes; Humans; Infant, Newborn; Lysosomal Storage Diseases; Male; Pedigree; Pregnancy; Prenatal Diagnosis; Risk
PubMed: 8825046
DOI: 10.1136/jmg.33.1.36 -
American Journal of Human Genetics Oct 1995Similarities in biochemical findings have suggested that Salla disease (SD) and the infantile form of sialic acid storage disease (ISSD) could represent allelic...
Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15.
Similarities in biochemical findings have suggested that Salla disease (SD) and the infantile form of sialic acid storage disease (ISSD) could represent allelic disorders, despite their drastically different clinical phenotypes. SD and ISSD are both characterized by lysosomal storage of free N-acetyl neuraminic acid. However, in SD the increase detected in urine is 8-24-fold, whereas in ISSD the corresponding amount is 20-50-fold and patients are also more severely affected. Here we report linkage studies in 50 Finnish SD families and 26 non-Finnish families with no genealogical connections to Finns affected either with the Finnish type of SD, the "intermediate" form of the disease, or ISSD. All forms of the disease show linkage to the same locus on 6q14-q15. Haplotype analyses of Finnish SD chromosomes revealed one common haplotype, which was also seen in most of the non-Finnish patients with Finnish type of SD. This ancestral haplotype deviated from those observed in ISSD patients, who had a different common haplotype.
Topics: Alleles; Chromosomes, Human, Pair 6; DNA, Satellite; Finland; Genetic Linkage; Haplotypes; Humans; Lod Score; Lysosomal Storage Diseases; N-Acetylneuraminic Acid; Phenotype; Polymorphism, Genetic; Sialic Acids; Sweden
PubMed: 7573051
DOI: No ID Found -
American Journal of Human Genetics Jun 1994Salla disease (SD), or adult-type free sialic acid storage disease, is an autosomal recessive lysosomal storage disorder characterized by impaired transport of free...
Salla disease (SD), or adult-type free sialic acid storage disease, is an autosomal recessive lysosomal storage disorder characterized by impaired transport of free sialic acid across the lysosomal membrane and severe psychomotor retardation. Random linkage analysis of a sample of 27 Finnish families allowed us to localize the SD locus to the long arm of chromosome 6. The highest lod score of 8.95 was obtained with a microsatellite marker of locus D6S286 at theta = .00. Evidence for linkage disequilibrium was observed between the SD locus and the alleles of three closely linked markers, suggesting that the length of the critical region for the SD locus is in the order of 190 kb.
Topics: Alleles; Child; Chromosome Mapping; Chromosomes, Human, Pair 6; Female; Finland; Genetic Markers; Humans; Linkage Disequilibrium; Lysosomal Storage Diseases; Male; Parents; Pedigree; Polymorphism, Genetic; Sialic Acids
PubMed: 8198127
DOI: No ID Found -
The Journal of Biological Chemistry Apr 1991Sialuria is a rare inborn error of metabolism caused by excessive synthesis of sialic acid (N-acetylneuraminic acid, NeuAc). Fibroblasts cultured from the three known...
Sialuria is a rare inborn error of metabolism caused by excessive synthesis of sialic acid (N-acetylneuraminic acid, NeuAc). Fibroblasts cultured from the three known cases of sialuria contained 70-200-fold increases in soluble sialic acid, but normal concentrations of bound sialic acid. The sialic acid appeared in the cytosolic fraction of the cells on differential centrifugation, and was susceptible to borohydride reduction, suggesting that accumulated sialic acid was in the form of NeuAc and not CMP-NeuAc. In biochemical studies, CMP-NeuAc (50 microM) inhibited the UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase of normal fibroblasts by 84-100%, but inhibited the epimerase from sialuria cells by only 19-31%. Feeding sialuria cells up to 5 mM D-glucosamine for 72 h increased free sialic acid content 20-60%, but normal cells were unaffected by this treatment. Cytidine feeding (5 mM, 72 h) reduced the NeuAc content of sialuria cells, initially 112, 104, and 266 nmol/mg protein, by 63-71 nmol/mg protein; CMP-NeuAc concentrations, initially 4, 2, and 5 nmol/mg protein, increased by 14-33 nmol/mg protein. Consequently, the total cellular content of soluble sialic acid (NeuAc + CMP-NeuAc) was lowered 14-46% by cytidine feeding. The inheritance pattern of sialuria has not been determined. However, cells from both parents of one sialuria patient contained normal concentrations of free sialic acid, and the parental epimerase activity also responded normally to CMP-NeuAc. We conclude that the basic biochemical defect in all known cases of sialuria is a failure of CMP-NeuAc to feedback-inhibit UDP-GlcNAc 2-epimerase and cytidine feeding can lower the intracellular soluble sialic acid concentration of sialuria cells.
Topics: Child, Preschool; Chromatography, High Pressure Liquid; Cytidine; Female; Fibroblasts; Humans; Male; Metabolism, Inborn Errors; N-Acetylneuraminic Acid; Sialic Acids
PubMed: 2019577
DOI: No ID Found