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At least 649 records · Page 36Linked to original sources
PubMed2003

Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns-/-) produced by targeted disruption of the gene defective in Morquio A disease.

Mucopolysaccharidosis IVA is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme required for the stepwise degradation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). To generate a model for studies of the pathophysiology and of potential therapies, we disrupted exon 2 of Galns, the homologous murine gene. Homozygous Galns-/- mice have no detectable GALNS enzyme activity and show increased urinary glycosaminoglycan (GAGs) levels. These mice accumulate GAGs in multiple tissues including liver, kidney, spleen, heart, brain and bone marrow. At 2 months old, lysosomal storage is present primarily within reticuloendothelial cells such as Kupffer cells and cells of the sinusoidal lining of the spleen. Additionally, by 12 months old, vacuolar change is observed in the visceral epithelial cells of glomeruli and cells at the base of heart valves but it is not present in parenchymal cells such as hepatocytes and renal tubular epithelial cells. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage. KS and C6S were more abundant in the cytoplasm of corneal epithelial cells of Galns-/- mice compared with wild-type mice by immunohistochemistry. Radiographs revealed no change in the skeletal bones of mice up to 12 months old. Thus, targeted disruption of the murine Galns gene has produced a murine model, which shows visceral storage of GAGs but lacks the skeletal features. The complete absence of GALNS in mutant mice makes them useful for studies of pharmacokinetics and tissue targeting of recombinant GALNS designed for enzyme replacement.

Animals↗
PubMed2005

Development of MPS IVA mouse (Galnstm(hC79S.mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disease caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. In recent studies of enzyme replacement therapy for animal models with lysosomal storage diseases, cellular and humoral immune responses to the injected enzymes have been recognized as major impediments to effective treatment. To study the long-term effectiveness and side effects of therapies in the absence of immune responses, we have developed an MPS IVA mouse model, which has many similarities to human MPS IVA and is tolerant to human GALNS protein. We used a construct containing both a transgene (cDNA) expressing inactive human GALNS in intron 1 and an active site mutation (C76S) in adjacent exon 2 and thereby introduced both the inactive cDNA and the C76S mutation into the murine Galns by targeted mutagenesis. Affected homozygous mice have no detectable GALNS enzyme activity and accumulate glycosaminoglycans in multiple tissues including visceral organs, brain, cornea, bone, ligament and bone marrow. At 3 months, lysosomal storage is marked within hepatocytes, reticuloendothelial Kupffer cells, and cells of the sinusoidal lining of the spleen, neurons and meningeal cells. The bone storage is also obvious, with lysosomal distention in osteoblasts and osteocytes lining the cortical bone, in chondrocytes and in the sinus lining cells in bone marrow. Ubiquitous expression of the inactive human GALNS was also confirmed by western blot using the anti-GALNS monoclonal antibodies newly produced, which resulted in tolerance to immune challenge with human enzyme. The newly generated MPS IVA mouse model should provide a good model to evaluate long-term administration of enzyme replacement.

Animals↗
PubMed1985

Purification and properties of galactosylceramide sulfatase activator from human liver.

Activator protein for galactosylceramide sulfatase (GSase) was purified from human liver. The activator has an approximate molecular weight of 22,000, is glycoprotein in nature, and is most probably a trimer consisting of an 8,000 dalton monomer. Monospecific rabbit antiserum raised against the activator strongly inhibited the activity of the activator. In the presence of a 10-fold or more excess of galactosylceramide sulfate (GS) on a molar basis, GS binding to the GSase activator occurred, and was saturated at an equimolar ratio. Binding studies on the GSase activator were conducted using affinity chromatography on derivatives of GS as ligands, and gel filtration of mixtures containing glycolipids and the activator. A "GS-acid" derivative, which was prepared by oxidative cleavage of sphingosine moiety in GS, and a sulfonamide derivative of GS as ligands still retained affinity for the GSase activator, while a hydrophobic ligands, an aminohexyl group did not bind completely the activator. A ligand of "galactosylceramide-acid" had weak affinity for GSase activator. These results suggest that the sulfate group and one of the two hydrocarbon chains in GS are not essential for the binding of the activator. The affinity of galactosylceramide for the GSase activator was confirmed by the detection of the lipid-protein complex on gel filtration. The activator weakly stimulated porcine GM1-beta-galactosidase activity.

Antigen-Antibody Complex↗
PubMed2005

Localization and gene expression of steroid sulfatase by RT-PCR in cumulus cells and relationship to serum FSH levels observed during in vitro fertilization.

BACKGROUND: The purpose of this study was to localize the expression of steroid sulfatase (STS) in cumulus cells and to determine the relationship between STS mRNA expression and the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol and progesterone. METHODS: The subject group included 49 women (29 to 44 years old) for whom in vitro fertilization treatment was indicated. All subjects gave informed consent. One hundred fourteen samples of cumulus-oocyte complex (COC) were obtained under microscopic observation. Part of the COC was stained by STS antibody. RNA was extracted by phenol-chloroform method and real-time PCR was performed. Serum of each patient was collected and was measured by ELISA. RESULTS: Some of the cumulus samples were stained by STS antibody. The expression of STS mRNA in all samples was confirmed by quantitative RT-PCR. Although there was no significant correlation between the level of STS mRNA and the serum levels of estradiol, progesterone and LH, there was a statistically significant negative correlation between the level of STS mRNA expression and the serum level of FSH (n = 105, p = 0.018, r = -0.22). CONCLUSION: These results have demonstrated for the first time the expression of STS in cumulus cells by immunohistological stainings and real-time RT-PCR. STS expression in cumulus cells may be related to the control of the local steroidal environment in the oocyte. Serum FSH may control STS mRNA expression from the results of RT-PCR, although the correlation was low.

Journal Article↗
PubMed2006

Ventral neural progenitors switch toward an oligodendroglial fate in response to increased Sonic hedgehog (Shh) activity: involvement of Sulfatase 1 in modulating Shh signaling in the ventral spinal cord.

In the embryonic chick ventral spinal cord, the initial emergence of oligodendrocytes is a relatively late event that depends on prolonged Sonic hedgehog (Shh) signaling. In this report, we show that specification of oligodendrocyte precursors (OLPs) from ventral Nkx2.2-expressing neural progenitors occurs precisely when these progenitors stop generating neurons, indicating that the mechanism of the neuronal/oligodendroglial switch is a common feature of ventral OLP specification. We further show that an experimental early increase in the concentration of Shh is sufficient to induce premature specification of OLPs at the expense of neuronal genesis indicating that the relative doses of Shh received by ventral progenitors determine whether they become neurons or glia. Accordingly, we observe that the Shh protein accumulates at the apical surface of Nkx2.2-expressing cells just before OLP specification, providing direct evidence that these cells are subjected to a higher concentration of the morphogen when they switch to an oligodendroglial fate. Finally, we show that this abrupt change in Shh distribution is most likely attributable to the timely activity of Sulfatase 1 (Sulf1), a secreted enzym that modulates the sulfation state of heparan sulfate proteoglycans. Sulf1 is expressed in the ventral neuroepithelium just before OLP specification, and we show that its experimental overexpression leads to apical concentration of Shh on neuroepithelial cells, a decisive event for the switch of ventral neural progenitors toward an oligodendroglial fate.

Animals↗
PubMed1980

Activities of N-acetylgalactosamine-6-sulfate sulfatase in liver from two sisters with morquio syndrome.

A 6-sulfated tetrasaccharide obtained by digesting chondroitin-6-sulfate with testicular hyaluronidase was used as a substrate for the determination of N-acetylgalactosamine-6-sulfate sulfatase activity. The activity was not detected in liver obtained from the elder sister with clinically classic Morquio syndrome and 4.7% of the control in liver from the younger sister with the same disease.

Adolescent↗
PubMed1984

Inhibition of steroid sulfatase activity by danazol.

The hydrolysis of dehydroepiandrosterone sulfate (DHAS) by human liver cells in culture and the hydrolysis of and formation of estradiol-17 beta (E2) from estrone sulfate (E1S) by human breast tumor preparations in vitro were studies in the presence and absence of danazol. In the latter tissue the effects of medroxyprogesterone acetate (MPA), trilostane, aminoglutethimide (AG) and tamoxifen were tested for comparison. Danazol at concentrations of 10(-6) - 1.4 X 10(-4) M strongly inhibited the hydrolysis of DHAS as well as the hydrolysis of and formation of E2 from E1S. With the exception of a slight inhibitory effect of trilostane upon E1S hydrolysis, the other four drugs did not inhibit the metabolism of E1S. Danazol, at concentrations corresponding to those occurring in vivo during therapy, is a potent inhibitor of steroid sulfatase activity. This may be one of the ways in which the drug affects peripheral and target tissue levels of steroid hormones.

Aminoglutethimide↗
PubMed1995

Mucopolysaccharidosis IVA: identification of a common missense mutation I113F in the N-Acetylgalactosamine-6-sulfate sulfatase gene.

Mucopolysaccharidosis IVA is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The recent isolation and characterization of cDNA and genomic sequences encoding GALNS has facilitated identification of the molecular lesions that cause MPS IVA. We identified a common missense mutation among Caucasian MPS IVA patients. The mutation was originally detected by SSCP, and successive sequencing revealed an A-->T transversion at nt 393. This substitution altered the isoleucine at position 113 to phenylalanine (I113F) in the 622 amino acid GALNS protein and was associated with a severe phenotype in a homozygote. Compound heterozygotes with one I113F-allele mutation have a wide range of clinical phenotypes. Transfection experiments in GALNS-deficient fibroblasts revealed that the mutation drastically reduces the enzyme activity of GALNS. Allele-specific oligonucleotide or SSCP analysis indicated that this mutation accounted for 22.5% (9/40) of unrelated MPS IVA chromosomes from 23 Caucasian patients, including 6 consanguineous cases. Of interest, the I1e 113-->Phe substitution occurred in only Caucasian MPS IVA patients and in none of the GALNS alleles of 20 Japanese patients. These findings identify a frequent missense mutation among MPS IVA patients of Caucasian ancestry, that results in severe MPS IVA when homoallelic, and will facilitate molecular diagnosis of most such patients and identification of heterozygous carriers. In addition to this common mutation, 10 different point mutations and 2 small deletions were detected, suggesting allelic heterogeneity in GALNS gene.

Base Sequence↗
PubMed1982

Administration of iduronate sulfatase by plasma exchange to patients with the Hunter syndrome: a clinical study.

The Hunter syndrome (MPS II) is the only mucopolysaccharidosis in which there is appreciable activity of the deficient enzyme in normal plasma. We performed enzyme-replacement treatment by plasma exchange in five Hunter syndrome children. Carefully monitoring the cardiovascular status, we administered monthly single plasma volume exchanges for a 3 to 8 mo period. The results indicate a substantial gain of enzyme activity, persisting with a t50% = 19 +/- 5 hr. The maximal level and persistence of increased enzyme activity did not change after repeated exchanges, suggesting that immune responses were not elicited. Despite this, no demonstrable clinical benefit was apparent when the study group was compared with an age-matched control group of Hunter syndrome patients.

Adolescent↗