Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early amniocentesis performed at 13 weeks gestation was utilized to obtain amniocytes for culture. Sonicates of cultured amniocytes were used to measure heparin sulfamidase activity for assessment of the status of an at risk pregnancy for Sanfilippo syndrome, type A. The heparin sulfamidase activity was not detectable in cultured amniocytes of the fetus at risk while another enzyme, N-acetylglucosamine 6-sulfatase, was comparable to that of the control. Following termination of the pregnancy, various tissue from the fetus were used for assay of both enzymes. The sulfamidase activity was not detectable in any of the fetal tissue while the 6-sulfatase activity was present in all fetal tissue but varied in activity depending on the type of tissue. Cultured fetal skin and brain contained the highest enzyme activity while skin and liver contained the lowest.
Biochem Mol Biol Int 1993 Apr
PMID:Prenatal diagnosis of Sanfilippo syndrome type A by early amniocentesis. 850 32

Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of sulfamidase. The resulting lysosomal storage of heparan sulfate may lead to severe neurodegeneration preceded by progressive dementia, often combined with aggressive and hyperactive behaviour. A total of 109 patients from four different geographic areas were screened for the common mutation R245H and two other previously identified mutations. SSCP analysis of exons was used to characterize the unknown alleles. We identified 16 novel sequence variants, 12 of them likely to be pathogenic. The majority of the pathogenic variants were single base pair changes leading to missense mutations. Several single base pair deletions/insertions and one nonsense mutation were also identified. Altogether, we were able to characterize 55% of the pathogenic alleles. Sequence homology between sulfamidase and N-acetylgalactosamine 4-sulfatase, the first sulfatase to have its tertiary structure defined, suggests that amino acid residues R74 and T79, which were found to be mutated, are likely to be involved in the formation of the active site of sulfamidase. R245H accounts for 31% of the Sanfilippo A alleles in Australasia, for 19.2% of the alleles in patients from the UK and has a high frequency of 57.8% in patients from The Netherlands. The identification of mutations common in certain geographic regions or ethnic groups will help in the diagnosis of MPS IIIA and allow carrier testing and improved genetic counselling.
Hum Mol Genet 1997 Sep
PMID:Novel mutations in Sanfilippo A syndrome: implications for enzyme function. 928 96

Mucopolysaccharidosis type IIIA (MPS-IIIA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of heparan-N-sulfamidase (NS; EC 3.10.1.1), resulting in defective degradation and subsequent storage of heparan sulfate and leading to a clinical phenotype known as Sanfilippo syndrome. A sensitive and specific monoclonal/polyclonal-based immunoquantification assay has enabled the determination of NS protein, down to approximately 3 pg NS protein, in cultured fibroblasts from control and MPS-IIIA patients. Cultured skin fibroblasts from 15 normal controls contained 11.9 to 105 ng of NS protein/mg extracted cell protein, whereas NS protein ranged from "none detected" to 11 ng/mg in fibroblasts from 35 MPS-IIIA patients. A relationship between genotype/phenotype and amount of NS protein present in these MPS-IIIA fibroblasts was established. Immunoquantification, in combination with a specific and highly sensitive tetrasaccharide-based assay of NS activity, enabled the determination of residual specific NS activity in these fibroblasts. Specific NS activity ranged from 28 to 1289 nmol/min/mg NS protein for MPS-IIIA patients, compared to 870 nmol/min/mg of recombinant human NS. It is proposed that this immunoquantification method, in conjunction with the specific NS activity assay, may be used to predict clinical severity in MPS-IIIA patients, allowing for the selection of individuals best suited for gene- and enzyme-replacement therapy when these methods become available. Also proposed is that an enzyme-replacement therapy achieving a correction of approximately 10% of normal NS activity is required to avoid the onset of a Sanfilippo clinical phenotype.
Mol Genet Metab 2001 Aug
PMID:Prediction of Sanfilippo phenotype severity from immunoquantification of heparan-N-sulfamidase in cultured fibroblasts from mucopolysaccharidosis type IIIA patients. 1150 12

The mucopolysaccharidoses (MPS) are lysosomal storage disorders resulting from the impaired catabolism of glycosaminoglycans (GAG). MPS type IIIA patients have dysfunctional sulfamidase enzyme leading to lysosomal storage of the GAG heparan sulfate, severe neurological symptoms including regression in learning, behavioural abnormalities, and premature death. We have engineered mouse D3 embryonic stem (ES) cells to over-express recombinant human sulfamidase. Human sulfamidase was correctly folded and secreted 2h post-labelling as determined by immunoprecipitation and SDS-PAGE analysis of transfected ES cells. Secreted human sulfamidase present in conditioned ES cell media was able to be taken up via mannose-6-phosphate-mediated endocytosis and restored sulfamidase enzyme activity in human MPS IIIA fibroblast cell lines. ES cells underwent directed differentiation to neural precursor populations and were capable of sustained human sulfamidase over-expression at all stages. Additionally, transfected and control cells were proliferative (Ki67+) and expressed several neural markers (nestin, MAP-2, and NF160) as determined by immunofluorescence. These findings suggest the possibility of ES cell-based therapy for the treatment of neurological pathology of MPS IIIA.
Mol Genet Metab 2004 Feb
PMID:In vitro characterization of genetically modified embryonic stem cells as a therapy for murine mucopolysaccharidosis type IIIA. 1474 Nov 88

Lysosomal storage disorders (LSD) are rare inherited metabolic diseases in which genetic alterations affect lysosomal proteins. Mucopolysaccharidosis type IIIA (MPS-IIIA) is an LSD characterized by reduced activity of sulfamidase (heparan-N-sulfatase, EC3.10.1.1), which degrades the sulfated glycosoaminoglycan heparan sulfate. The central nervous system (CNS) is the main site of pathology in MPS-IIIA, resulting in reduced neurological function and neurocognitive decline. Neuropathological changes include lysosomal vacuolation of heparan sulfate and lipids in neurons, glia, and perivascular cells and the formation of axonal spheroids and ectopic dendrites. At present there is no effective treatment for the CNS effects of LSD as enzyme administered intravenously cannot cross the blood-brain barrier. We have previously established and characterized a mouse model of MPS-IIIA, and in the present study, we injected recombinant human sulfamidase directly into the brain at 6, 12 or 18 weeks of age. Treatment reduced vacuolation and gliosis and delayed the onset of ubiquitin-positive neurodegenerative changes in widespread areas of MPS-IIIA brain, assessed at 24 weeks of age. However, ubiquitin-positive axonal spheroids already detectable by 6 weeks of age were unaffected by treatment at any age, suggesting their irreversibility and thus indicating the importance of early detection of MPS-IIIA and instigation of therapy.
Mol Genet Metab 2004 Aug
PMID:Intracerebral injection of sulfamidase delays neuropathology in murine MPS-IIIA. 1530 25

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by a deficiency in the lysosomal enzyme sulfamidase, which is required for the degradation of heparan sulfate. The disease is characterized by neurological dysfunction but relatively mild somatic manifestations. A naturally occurring mouse model to MPS IIIA exhibits a similar disease progression to that observed in patients. Disease in the mice results from a base substitution at codon 31 in the sulfamidase gene, altering an aspartic acid to an asparagine (D31N). This aspartic 31 is involved in binding of the divalent metal ion needed for catalytic function, and as such reduces the specific activity of the enzyme to about 3% of that of wild-type. The mutant protein has decreased stability and shows increased degradation over a 24 h chase period when compared to wild-type mouse sulfamidase. Mouse sulfamidase that was purified using a two-step ion exchange procedure was shown to have similar kinetic properties to that of purified human sulfamidase. Recombinant murine sulfamidase was able to correct the storage phenotype of MPS IIIA fibroblasts after endocytosis via the mannose-6-phosphate receptor.
Mol Genet Metab 2004 Nov
PMID:Purification and characterization of recombinant murine sulfamidase. 1554 95

Mucopolysaccharidosis IIIA (MPS IIIA; Sanfilippo syndrome) is an autosomal recessive lysosomal disorder caused by the deficiency of sulfamidase (EC 3.10.1.1), required for the degradation of the mucopolysaccharide heparan sulfate. The molecular defects of 26 unrelated Spanish MPS IIIA patients were recently reported by our group. Here we describe the heterologous expression, using a baculovirus system, of the cDNAs corresponding to eight out of the 14 mutant alleles present in this patient group and the characterization of the corresponding mutant enzymes. In particular, we expressed the following alleles: p.S66W, p.R74H, p.Q85R, p.R206P, p.L386R, p.R433W, p.R433Q, and c.1079delC (previously named as c.1091delC), and the two variants of the polymorphism p.R456H. The expression of the mutant alleles and the characterization of the corresponding enzymes revealed that their activity was severely compromised. Only mutations p.S66W and p.R206P retained low levels of residual activity. However, Western blot analysis showed in all cases the presence of the expected two forms of the sulfamidase, the precursor and the mature proteins, indicating a normal processing of the mutant enzyme.
Mol Genet Metab 2004 Nov
PMID:Expression and functional characterization of human mutant sulfamidase in insect cells. 1554 96

Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder resulting from sulfamidase deficiency, which leads to accumulation of heparan sulfate within lysosomes. We have determined the time-course of accumulation of a disaccharide [hexosamine-N-sulfate[alpha-1,4]hexuronic acid; HNS-UA] marker of heparan sulfate storage within the brain, liver, and spleen of a naturally occurring mouse model of MPS IIIA. HNS-UA is detectable in the brain of affected mice on the day of birth, when it is significantly increased compared to normal control mice. As mice age, this compound steadily accumulates until a plateau is reached at approximately 20-weeks. A similar rate of accumulation of HNS-UA is seen in the liver and spleen of affected mice. Intracerebral delivery of recombinant human sulfamidase reduced the amount of HNS-UA present in segments of the brain receiving the correcting enzyme, thus demonstrating the effectiveness of enzyme replacement therapy within the central nervous system of affected mice. This finding therefore provides evidence for the use of the disaccharide HNS-UA to monitor the effect of therapies for this condition in humans, when treatment strategies are devised.
Mol Genet Metab 2006 Feb
PMID:Validation of a heparan sulfate-derived disaccharide as a marker of accumulation in murine mucopolysaccharidosis type IIIA. 1635 54

Lysosomal storage disorders (LSD) are chronic progressive diseases that have a devastating impact on the patient and family. Most patients are clinically normal at birth but develop symptoms early in childhood. Despite no curative treatment, a number of therapeutic options are available to improve quality of life. To achieve this, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology. We have developed a multiplexed immune-quantification assay of 11 different lysosomal proteins for the identification of individuals with an LSD and evaluated this assay in a retrospective study using blood-spots from; newborns subsequently diagnosed with an LSD (n=19, six different LSD), individuals sampled after diagnosis of an LSD (n=92, 11 different LSD), newborn controls (n=433), and adult controls (n=200). All patients with mucopolysaccharidosis type I (MPS I), MPS II, MPS IIIA, MPS VI, metachromatic leukodystrophy, Niemann-Pick disease type A/B, and multiple sulfatase deficiency could be identified by reduced enzyme levels compared to controls. All mucolipidosis type II/III patients were identified by the elevation of several lysosomal enzymes, above the control range. Most Fabry, Pompe, and Gaucher disease patients were identified from either single protein differences or profiles of multiple protein markers. Newborn screening for multiple LSD is achievable using multiplexed immune-quantification of a panel of lysosomal proteins. With further validation, this method could be readily incorporated into existing screening laboratories and will have a substantial impact on patient management and counseling of families.
Mol Genet Metab 2006 Aug
PMID:Newborn screening for lysosomal storage disorders. 1660 Jun 51

At present, there is no widely available, safe and effective treatment for lysosomal storage disorders (LSD) that affect the brain. We have used a naturally occurring mouse model of mucopolysaccharidosis type IIIA (MPS IIIA) or Sanfilippo syndrome, to evaluate the effect of repeated injection of recombinant human sulfamidase (rhSGSH) into the cerebrospinal fluid via the cisterna magna (CM) on central nervous system (CNS) pathology and behavioral function. Mice received up to seven injections of rhSGSH (5-20 microg rhSGSH per injection) or vehicle on a fortnightly or monthly basis. A dose-dependent reduction in the level of a heparan sulfate-derived monosulfated disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated MPS IIIA mice) and spinal cord (up to 71% reduction). Ultrastructural examination revealed a reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) axonal spheroids were observed in several brain regions. The biochemical changes were accompanied by improved behavior, particularly in mice-treated more frequently. A humoral immune response to rhSGSH was observed in treated animals. Intra-CM injection of lysosomal enzyme may therefore represent an immediately applicable method of treating the CNS effects of this and potentially other LSD that affect the brain.
Mol Genet Metab 2007 Mar
PMID:Injection of recombinant human sulfamidase into the CSF via the cerebellomedullary cistern in MPS IIIA mice. 1716 57


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