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At least 469 records · Page 26Linked to original sources
PubMed1993

The mouse iduronate sulfatase gene: identification of a novel transcript.

Complementary DNAs, cDNAs, coding for iduronate sulfatase (IDS, E.C.3.1.6.13) have been isolated and characterized in man and mouse. The murine cDNA (MTA16) was highly homologous to the human counterpart. By screening the same mouse thymus cDNA library another cDNA (MTA13) was isolated: it is 1831 bp long and is identical to a part of the MTA16 cDNA in its 5' region, but it is completely divergent in the 3' region. Characterization of the MTA13 mRNA as well as its genomic organization are presented. The results herein reported support the hypothesis that MTA13 and MTA16 mRNAs are encoded by the same gene.

Amino Acid Sequence↗
PubMed1999

Structure-activity relationship study of steroidal and nonsteroidal inhibitors of the enzyme estrone sulfatase.

We report the initial results of a series of molecular modelling studies to investigate the structural properties of non-steroidal inhibitors required for inhibitory activity against the enzyme estrone sulfatase (ES) [the enzyme responsible for the conversion of nonactive (sulfated) estrone to the active (nonsulfated) estrone]. From the results of the present study, we conclude that the C(17) polar group may not be necessary for inhibitory activity and that the only requirement appears to be the mimicking of the steroid C(3) sulfonate group. To test our hypotheses, we have designed novel straight chain inhibitors based upon alkyl alcohols, which upon evaluation, have been shown to possess inhibitory activity (e.g., an inhibitor based upon trichloroethanol has been shown to possess 46% inhibition at 0.76mM).

Enzyme Inhibitors↗
PubMed2000

First report of the investigation into the importance of pK(a) in the inhibition of estrone sulfatase by sulfamate containing compounds.

In an effort to rationalise the inhibitory activity of a range of aminosulfamate compounds and to further investigate the recently reported definitive pharmacophore estrone sulfatase (ES), we undertook extensive synthesis, biochemical evaluation and physicochemical property determination of a range of similar compounds. Here, we report the initial results of our study into a series of simple (aminosulfonate based) substituted phenol derivatives. Using these compounds, we investigated the role of pK(a) in the inhibition of ES. The results of the study suggest that there is a strong correlation between the inhibitory activity and the stability of the resulting O(-) anion (i.e., the pK(a) of the starting phenol).

Anions↗
PubMed1993

Sequence of the human iduronate 2-sulfatase (IDS) gene.

Deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS; EC 3.1.6.13) results in the storage of the glycosaminoglycans heparan sulfate and dermatan sulfate, which leads to the lysosomal storage disorder mucopolysaccharidosis type II. Three overlapping genomic clones derived from an X-chromosome-specific library containing the entire IDS gene were isolated and the sequences of the intron boundaries and the 5' promoter region were determined. The IDS gene is split into nine exons spanning approximately 24 kb. The potential promoter for IDS lacks a TATA box but contains GC box consensus sequences, consistent with its role as a housekeeping gene. A polypyrimidine-like repeat is found in intron 1.

Base Sequence↗
PubMed1993

A yeast artificial chromosome contig linking the steroid sulfatase and Kallmann syndrome loci on the human X chromosome short arm.

In this report we describe the construction of a yeast artificial chromosome (YAC) contig linking the steroid sulfatase (STS) and Kallmann syndrome (KAL) loci on Xp22.3. Four human YAC libraries were screened initially with sequences from DXS237 (GMGX9), DXS278 (S232B), and KAL and later with primers from exon 10 of the STS gene and the end fragment of a YAC clone YGX3 to fill the gaps. Fifteen clones were isolated and the sizes of their human inserts were determined by pulsed-field gel electrophoresis followed by Southern hybridization with labeled total human DNA. Overlaps between the YAC clones were evaluated using more than 20 DNA markers, including the screening probes, the end fragments, and the Alu-PCR products of the YAC clones. The extent of overlapping between the clones was further determined by long-range restriction mapping. In combination with our previously reported YAC contigs around STS and KAL, a total of 2 Mb of Xp22.3 have been isolated in YAC clones. These clones will facilitate the isolation of new genes and the characterization of deletions and translocations which occur at very high frequency in this region of the human X chromosome.

Arylsulfatases↗
PubMed1995

Identification of an alternative transcript from the human iduronate-2-sulfatase (IDS) gene.

Iduronate-2-sulfatase (IDS) is involved in the degradation of heparan sulfate and dermatan sulfate in the lysosomes, and a deficiency in this enzyme results in Hunter syndrome. A 2.3-kb cDNA clone that contains the entire coding sequence of IDS has previously been reported. Here we describe the identification of a 1.4-kb transcript that may encode an IDS-like enzyme. The predicted protein is identical to the previously described enzyme, except for the absence of the 207-amino-acid COOH-terminal domain, which is replaced by 7 amino-acids. Our data suggest that there might exist an additional form of the IDS enzyme in humans. The results from this study may have implications for the pathogenesis of the Hunter syndrome.

Alternative Splicing↗
PubMed2001

Steroid sulfatase expression in ovarian clear cell adenocarcinoma: immunohistochemical study.

OBJECTIVE: Steroid sulfatase (STS) is an important enzyme that converts biological inactive steroid sulfate to active free steroid. As estrogen is thought to play an important role in cell proliferation in gynecological cancer, the existence of STS may have particular significance in the prognosis of ovarian cancer. In the present study, we determined the STS expression of ovarian clear cell adenocarcinoma (OCCA), which has the poorest prognosis among various ovarian cancers, immunohistochemically to clarify the biological nature of OCCA and also to determine whether STS expression is one of the prognostic factors in OCCA. METHODS: Forty-five archival, formalin-fixed, paraffin-embedded tissues from patients with OCCA and other epithelial ovarian cancers who were first operated on from 1987 to 1998 were subjected to analysis. Twenty-eight of forty-five (60.9%) OCCA cases coexisted with endometriosis. They were subclassified into papillary, solid, and tubulocystic types with respect to architectural pattern. Immunohistochemical staining of STS was performed using anti-human STS polyclonal rabbit antibody that had been immunized with purified STS from human placenta. RESULTS: STS was immunohistochemically stained positively in 70% (32/45) of OCCA, 33.3% of serous adenocarcinoma (6/18), and 50.0% of mucinous adenocarcinoma (4/8) specimens and was localized in the cytoplasm of neoplastic epithelial cells. No significant relationship was found between STS staining and FIGO staging. However, patients diagnosed as papillary type had a significantly lower survival rate and showed significantly more positive staining of STS (P < 0.05) than those with solid type. Stage, STS expression, and architectural type yielded a significant association with survival rate. CONCLUSION: It was proven that STS is present in the cytoplasm of patients with OCCA by an immunohistochemical method. OCCA patients with papillary tumor with positive STS expression are considered to have a poor prognosis.

Adenocarcinoma, Clear Cell↗
PubMed2000

"Supercharged Cells" for delivery of recombinant human iduronate-2-sulfatase.

Expression of iduronate-2-sulfatase (IDS) from three different promoters in four retroviral vectors was studied in peripheral blood lymphocytes from patients with Hunter syndrome (PBL(MPS)), i.e., the LTR in vectors L2SN and L2, avian beta-actin promoter in LB2, and the CMV early promoter in LNC2. PBL(MPS) were exposed to packaging cell supernatant resulting in transduction frequencies ranging 10-fold from 5 to 49%. Surprisingly, IDS activities were equally high in all transduced lymphocyte populations: 515 U/mg/h in PBL(MPS)-L2SN, 734 in PBL(MPS)-LB2, 352 in PBL(MPS)-L2, and 389 in PBL(MPS)-LNC2 compared to controls (<10 in PBL(MPS)-LXSN or PBL(MPS)). The half-life of endocytosed IDS in PBL(MPS) was 1.9 days. However, the level of lymphocyte IDS activity from proviral expression was found to be only a fraction of the total, a large portion being derived from reuptake of enzyme from murine packaging cells, i.e., a "second source" of enzyme. Therefore, measurement of transgene lysosomal enzyme soon after exposure of target cells to vector supernatant may yield a gross overestimate of long-term transgene expression by transduced cells. Nevertheless, patient fibroblasts cocultured with transduced PBL(MPS) had reduced (35)SO(4)-GAG accumulation, levels similar to those of normal fibroblasts. These studies revealed a broadly applicable phenomenon: cells can be charged with a lysosomal enzyme to levels much higher than those found in nature. By "supercharging" cells with a lysosomal protein (or other molecule bearing the mannose-6-phosphate ligand), such cells may be exploited as vehicles for systemic delivery of therapeutic or diagnostic agents.

Cells, Cultured↗
PubMed1992

Assessment of iduronate-2-sulfatase mRNA expression in Hunter syndrome (mucopolysaccharidosis type II).

Eight unrelated patients with Hunter syndrome were investigated for expression of iduronate-2-sulfatase (IDS) mRNA by reverse transcription (RT) linked to polymerase chain reaction (PCR), or RT-PCR. The entire coding region was studied by amplification of two overlapping segments of 0.7 and 1.1 kb. Seven children with Hunter syndrome had PCR products indistinguishable in size from normal. One patient, with clinically severe disease, did not produce either IDS product although mRNA for a control gene was readily amplified. This method rapidly identifies patients having absent or qualitatively abnormal IDS mRNA and may be useful in investigating genotype-phenotype relationships.

Base Sequence↗
PubMed1995

Evidence for an iduronate-sulfatase pseudogene near the functional Hunter syndrome gene in Xq27.3-q28.

We are currently characterizing mutations of the iduronate-2-sulfatase (IDS) gene in patients with Hunter syndrome (mucopolysaccharidosis type II). Surprisingly, all 17 patients with a mutation in exon III of the IDS gene identified by us were found to carry both the mutant and wild-type sequences in polymerase chain reaction (PCR) products amplified from genomic DNA. Similarly, two unaffected male controls showed a heterozygous pattern for two different point mutations in exon III. Collectively, the data suggest that at least intron 2, exon III, and the 3'-half of exon II of the functional IDS gene are present in the human genome as (part of) a non-expressed IDS gene. Deletion mapping further suggests that the pseudogene is in distal Xq in physical proximity to the functional IDS gene. The high degree of sequence homology observed between the functional IDS gene and pseudogene results in permanent co-amplification in PCR-based screening methods and makes mutation analysis at the genomic DNA level difficult.

Base Sequence↗
PubMed1979

Urinary acid mucopolysaccharides in multiple sulfatase deficiency (mucosulfatidosis).

Urinary acid mucopolysaccharides (AMPS) excretion was investigated in a Japanese case with Multiple Sulfatase Deficiency (MSD) (Mucosulfatidosis). The patient excreted AMPS 4 to 5 times more (as carbazoluronic acid) than controls. The cellulose acetate gel electrophoresis clearly indicated two major AMPS which co-migrated with heparan sulfate and chondroitin sulfate A/C. Enzymic digestion with chondroitinase AC and ABC, and by testicular hyaluronidase plus amino sugar analysis also confirmed that our case excreted heparan sulfate and chondroitin sulfate A/C. These findings suggest that there are heterogeneities of urinary AMPS excretion among cases with MSD.

Child↗
PubMed1986

Late-onset Krabbe disease initially diagnosed as cerebroside sulfatase activator deficiency.

Clinical and biochemical findings in a male subject with progressive encephalopathy and peripheral neuropathy are presented. Early development was normal. At age 3.5 years, he had seizures associated with fever. Subsequently, there was progressive neurologic deterioration. A CT brain scan at age 4 years, 2 months demonstrated multiple areas of variable density in the white matter. There was mild slowing of nerve conduction velocities and a sural nerve biopsy revealed segmental demyelinative neuropathy. Metachromatic leukodystrophy was suspected, but arylsulfatase A activity in leukocytes and fibroblasts was in the normal range. The cerebroside sulfate loading test on intact cultured fibroblasts showed attenuated hydrolysis leading to a tentative diagnosis of cerebroside sulfatase activator deficiency. However, the attenuated response of proband fibroblasts was not normalized by supplementation with activator in a reproducible manner, and urine showed hyperexcretion rather than deficiency of activator. Ultimately, an assay for galactosylceramide beta-galactosidase activity established a deficiency of this enzyme leading to the diagnosis of late-onset Krabbe disease.

Cerebroside-Sulfatase↗
PubMed1991

Mammalian sex chromosomes. III. Activity of pseudoautosomal steroid sulfatase enzyme during spermatogenesis in Mus musculus.

Parallel to the inactivation of the X chromosome in somatic cells of female, the male X in mammals is rendered inactive during spermatogenesis. Pseudoautosomal genes, those present on the X-Y meiotically pairable region of male, escape inactivation in female soma. It is suggested, but not demonstrated, that they may also be refractory to the inactivation signal in male germ cells. We have assayed activity of the enzyme steroid sulfatase, product of a pseudoautosomal gene, in testicular cells of the mouse and shown its presence in premeiotic, meiotic (pachytene), and postmeiotic (spermatid) cell types. It appears that, as in females, pseudoautosomal genes may escape inactivation in male germ cells also.

Animals↗
PubMed1994

Cervical cord compression and severe hydrocephalus in a child with Saudi variant of multiple sulfatase deficiency. Report of case.

We report a 2.5-year-old boy with Saudi variant of multiple sulfatase deficiency (MSD or Austin's disease). He presented with the features of cervical cord compression and a severe form of hydrocephalus. The former was due to a thickened posterior arch of the atlas and the latter from a narrow foramen magnum and meningeal thickening. Decompression of the cord was achieved by removal of the posterior margin of the foramen magnum and posterior arch of the atlas, and followed by a duroplasty. At a later date, ventricular decompression was achieved by insertion of a ventricular-peritoneal shunt. NMR did not demonstrate white matter changes in the brain. In this regard the reported case differs from the earlier description of the Saudi Variant of MSD.

Brain↗
PubMed1993

Steroid sulfatase deficiency in Japanese patients: characterization of X-linked ichthyosis by using polymerase chain reaction.

X-Linked ichthyosis (XLI) due to deficiency of steroid sulfatase (STS) of which gene consists of 10 exons is an inherited skin disorder. The gene, mRNA and protein of STS were examined in six Japanese patients with XLI. Neither the mRNA nor the enzyme protein was detected in a patient. The results of Southern analysis using STS cDNA as a probe indicated that all the patients examined exhibited large deletions of the STS gene. When exon 1 and the exon 10 of the STS gene were amplified by polymerase chain reaction using patients' genomic DNA as templates, no product was detected in all the patients examined. These observations suggest that most XLI in Japanese patients is caused by an extensive deletion of the STS gene as was demonstrated in Caucasian patients. The PCR method in the present study is useful for the diagnosis of XLI in prenatal and postnatal subjects.

Arylsulfatases↗
PubMed1996

Mutations in the iduronate-2-sulfatase gene in five Norwegians with Hunter syndrome.

We have identified the mutations in the iduronate-2-sulfatase (IDS) gene of five unrelated Norwegians with Hunter syndrome by reverse transcription-polymerase chain reaction (RT-PCR) analysis of IDS mRNA followed by single strand conformation polymorphism (SSCP) analysis and cDNA sequencing. One patient had a 5-bp deletion, located at the intron 5/exon 6 junction, that created a new alternative splice site. This expanded the deletion to 9 bp in mRNA, an in-frame deletion of the first 3 codons of exon 6 of the IDS gene. In two patients point mutations were identified, the S333L mutation, which has been reported previously, and A346D (a C-->A transversion at nucleotide 1161/exon 8), which is novel. Two patients had large 3' mRNA rearrangements. The A346D mutation was associated with the mild phenotype, all others with the severe form.

Adolescent↗
PubMed1996

Characterization of the promoter region of human steroid sulfatase: a gene which escapes X inactivation.

The human X-linked steroid sulfatase gene (STS) was among the first genes shown to escape X inactivation. At least fourteen genes regulated in this fashion have now been recognized. They are dispersed into several regions of the X chromosome and may be controlled in a locus specific manner. Studies of the promoters of these genes could provide insights into the mechanism of X inactivation, however little information of this nature is currently available. For this reason we examined 5' flanking sequences of the human STS gene for promoter function. Four transcription start sites scattered over a 50bp region were identified. Functional domains of this TATA-less and GC poor promoter were identified by study of a series of terminal and internal deletions. A putative promoter sequence was identified which by itself exhibits little or no basal activity. However when combined with upstream regulatory elements, this segment showed weak but reproducible activity in a CAT (chloramphenicol acetyltransferase) reporter assay. Several regulatory domains acting as enhancers and repressors were subsequently identified. The relationship of this 5' sequence to the ability of the STS gene to escape X-inactivation is discussed.

Arylsulfatases↗
PubMed1998

Mutational spectrum of the iduronate-2-sulfatase (IDS) gene in 36 unrelated Russian MPS II patients.

We present a mutational analysis of the iduronate-2-sulfatase (IDS) gene of 36 Russian patients with Hunter syndrome. Among 29 mutant alleles, there were 19 missense mutations, 1 nonsense mutation, 6 mutations affecting splice sites, and 3 major structural alterations resulting in deletions. Of the 25 different mutations, 15 are novel and unique. Most of the missense mutations result in intermediate or severe phenotypes.

Blotting, Southern↗