Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Scanning methodologies are used for the identification of DNA fragments that differ from the normal nucleotide sequence. Fragments that produce abnormal band patterns are sequenced for characterization of the exact mutation. Factors considered in choosing a scanning methodology include reproducibility, sensitivity, and time. In the present study, we compared single-stranded conformational polymorphism (SSCP) and Cleavase fragment length polymorphism (CFLP) methodologies for mutation scanning of exon VIII in the iduronate 2-sulfatase (IDS) gene. Mutations of the IDS gene result in an X-linked lysosomal storage disease, Hunter syndrome. These six known mutations analyzed by the two methods included a one base pair deletion, a one base pair insertion, and four point mutations. SSCP analysis detected all of the mutations and CFLP analysis detected three of the six mutations. We concluded that SSCP analysis was preferable to CFLP analysis for scanning exon VIII in the IDS gene for mutations.
Biochem Mol Biol Int 1997 Dec
PMID:Comparison of SSCP analysis and CFLP analysis for mutation detection in the human iduronate 2-sulfatase gene. 944 13

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a lysosomal disease caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS, EC 3.1.6.13). Affected patients show a wide spectrum of clinical phenotypes, from severe to mild. Mutational analysis on this disease resulted in the identification of more than 200 alterations. Bone marrow transplantation (BMT) is considered, at present, an appropriate therapy for MPS II subjects without severe neuropsychological impairment, however molecular analysis in BMT treated patients has been poorly studied. We describe here a patient subjected to BMT in 1995 whose IDS gene alteration, mutation P266H, was identified thereafter. The 4-year follow-up included clinical, biochemical and molecular parameters. DNA analysis showed, after BMT, coexisting host mutant and donor normal alleles, ensuring the effectiveness of the therapy and providing a fast and accurate tool to monitor the colonization of donor cells after treatment.
Int J Mol Med 1999 Oct
PMID:Bone marrow transplantation in a Hunter patient with P266H mutation. 1049 87

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.
Mol Genet Metab 2000 Jul
PMID:"Supercharged Cells" for delivery of recombinant human iduronate-2-sulfatase. 1092 71

DNA inversions are mutations involving major rearrangements of the genome and are often regarded as either deleterious or catastrophic to gene function and can be associated with genomic disorders, such as Hunter syndrome and some forms of hemophilia. Here, we propose that DNA inversions are also an essential and hitherto unrecognized component of gene evolution in eukaryotic cells. Specifically, we provide evidence that an ancestral neuronal nitric oxide synthase (nNOS) gene was duplicated and that one copy retained its original function, whereas an internal DNA inversion occurred in the other. Crucially, the inversion resulted in the creation of new regulatory elements required for the termination and activation of transcription. In consequence, the duplicated gene was split, and two new and independently expressed genes were created. Through its dependence on DNA inversion, this is a fundamentally new scheme for gene evolution, which we show as being of particular relevance to the generation of endogenous antisense-containing RNA molecules. Functionally, such transcripts can operate as natural negative regulators of the expression of the genes to which they are related through a common ancestor.
Mol Biol Evol 2002 Aug
PMID:Evolution of nitric oxide synthase regulatory genes by DNA inversion. 1214 Feb 34

The mucopolysaccharidoses are a group of lysosomal storage disorders characterised by the storage of glycosaminoglycans. With the exception of Hunters syndrome (MPS II), which is X-linked, they are autosomal recessively inherited resulting in a defect in any one of 10 lysosomal enzymes needed to catabolise glycosaminoglycans. The type and size of the glycosaminoglycans stored in lysosomes are determined by the particular enzyme deficiency. These glycosaminoglycan elevations are subsequently observed in tissue, circulation, and urine. A method has been developed for the derivatisation and quantification of sulfated N-acetylhexosamine-containing mono- and disaccharides from patient samples by electrospray ionisation tandem mass spectrometry. Urine from most mucopolysaccharidoses types had significant increases in di- and monosulfated N-acetylhexosamines (GalNAc4,6S, GalNAc6S, GalNAc4S, or GlcNAc6S) and monosulfated N-acetylhexosamine-uronic acid disaccharides (GalNAc6S-UA, GalNAc4S-UA, or GlcNAc6S-UA). Analysis of plasma and dried blood spots on filter paper collected from mucopolysaccharidoses patients showed elevations of total monosulfated N-acetylhexosamines but less than that seen in urine. Urine samples from bone marrow transplant recipients, mucopolysaccharidosis IVA and mucopolysaccharidosis VI patients, showed decreases in HexNAcS, HexNAcS(2)/GalNAc4,6S, and HexNAcS-UA post-transplant. This decrease correlated with clinical improvement to levels comparable with those identified in patients with less severe phenotypes. These metabolic markers therefore have potential applications in diagnosis, phenotype prediction and monitoring of current and future therapies, particularly for the mucopolysaccharidosis IIID, IVA, VI, and multiple sulfatase deficiency. This paper reports a sensitive and simple method for the measurement of sulfated N-acetylhexosamines and sulfated disaccharides shown to be elevated in some mucopolysaccharidosis and multiple sulfatase deficient patients.
Mol Genet Metab 2003 Mar
PMID:Determination of monosaccharides and disaccharides in mucopolysaccharidoses patients by electrospray ionisation mass spectrometry. 1264 64

The lysosomal storage disorder mucopolysaccharidosis type II (MPS II) is caused by a deficiency in the activity of the lysosomal exohydrolase iduronate-2-sulphatase (IDS). MPS II patients present within a spectrum of clinical phenotypes, which reflects the dynamic balance between the level of mutant protein, its residual enzyme activity and the resultant level of storage product. In this study, we have developed an immunoquantification assay for the accurate detection of iduronate-2-sulphatase protein and applied this methodology to the analysis of mutant iduronate-2-sulphatase protein in plasma samples from MPS II patients. The detection limit for the assay was defined as 20 ng/ml for wild type iduronate-2-sulphatase, but could be extended to a detection limit of 0.3 ng/ml by heat denaturation of the protein/plasma sample. The mutant protein detected in plasma from MPS II patients displayed similar properties to heat denatured wild type iduronate-2-sulphatase, suggesting an altered protein conformation. The ratio of heat denatured to native ELISA reactivity could be used to confirm the diagnosis of MPS II (i.e., a ratio of >1 for normal protein and <or=1 for mutant protein). Notably, four of the 20 patients tested had either normal or higher than normal levels of iduronate-2-sulphatase protein, but this protein also showed evidence of conformation change. The iduronate-2-sulphatase protein level detected in plasma from MPS II patients showed little or no direct correlation with the severity of the clinical phenotype observed in these patients.
Mol Genet Metab 2004 Jan
PMID:Iduronate-2-sulphatase protein detection in plasma from mucopolysaccharidosis type II patients. 1472 92

Hematopoietic stem cell transplant (HSCT) has been performed on patients with Hunter's syndrome. If applied, evaluation of recovery in various organs is needed for long-term follow-up. However, it remains unclear whether HSCT is effective against the neurological involvement in Hunter's syndrome, and morphological evaluation of recovery is inconsistent. We observed the degree of cutaneous nerve involvement in patients with Hunter's syndrome ultrastructurally before and after HSCT. Electron microscopic studies revealed that membrane-bound clear vacuoles were still observed in the cytoplasm of endoneurial fibroblasts and Schwann cells 2 months and 2 years, respectively, after HSCT. On the other hand, only a few vacuoles were present in dermal fibroblasts at 2 months after HSCT, and these disappeared within 2 years. These results suggest that the persistence of clear vacuoles in endoneurial fibroblasts and Schwann cells indicates a disturbed internal condition in the endoneurium 2 years after HSCT. Skin biopsies can be used in patients with Hunter's syndrome to study peripheral nerves for long-term follow-up to evaluate morphological efficacy.
Med Mol Morphol 2005 Jun
PMID:Ultrastructural findings of cutaneous nerves in patients with Hunter's syndrome following hematopoietic stem cell transplant. 1594 19

Mucopolysaccharidosis type II (MPSII; Hunter syndrome) is a lysosomal storage disorder caused by a deficiency in the enzyme iduronate 2-sulfatase (IDS). At present, the therapeutic approaches for MPSII are enzyme replacement therapy and bone marrow transplantation, although these therapies have some limitations. The availability of new AAV serotypes that display tissue-specific tropism and promote sustained expression of transgenes offers the possibility of AAV-mediated gene therapy for the systemic treatment of lysosomal diseases, including MPSII. We have characterized in detail the phenotype of IDS-deficient mice, a model of human MPSII. These mice display a progressive accumulation of glycosaminoglycans (GAGs) in many organs and excessive excretion of these compounds in their urine. Furthermore, they develop skeleton deformities, particularly of the craniofacial bones, and alopecia, they perform poorly in open-field tests and they have a severely compromised walking pattern. In addition, they present neuropathological defects. We have designed an efficient gene therapy approach for the treatment of these MPSII mice. AAV2/8TBG-IDS viral particles were administrated intravenously to adult MPSII mice. The plasma and tissue IDS activities were completely restored in all of the treated mice. This rescue of the enzymatic activity resulted in the full clearance of the accumulated GAGs in all of the tissues analyzed, the normalization of the GAG levels in the urine and the correction of the skeleton malformations. Overall, our findings suggest that this in vivo gene transfer approach has potential for the systemic treatment of patients with Hunter syndrome.
Hum Mol Genet 2006 Apr 01
PMID:Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery. 1650 2

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

Mutations in the gene encoding the enzyme iduronate-2-sulfatase (IDS) were reported as the cause of the X-linked recessive lysosomal disease, mucopolysaccharidosis II (MPS II). Amongst the different mutations, it emerges that nearly 10% are nucleotide substitutions causing splicing mutations. We now report the molecular characterisation of three MPS II patients with multiple aberrant transcripts due to three different point mutations. The c.418+1G>C that occurred in the invariant splice-site motif, produced only aberrantly spliced transcripts. Whilst the mutations affecting variant motifs (c.419G>T) or coding regions (c.245C>T) led to aberrantly spliced transcripts in addition to correctly spliced transcripts with the respective predicted missense mutation, p.G140V or p.A82V. A combination of experimental tests and computational approaches were used to understand the molecular basis underlying the altered transcription patterns. In addition, by using real-time reverse transcriptase polymerase chain reaction, the reduction of mRNA amount in two patients observed was likely due to nonsense-mediated mRNA decay pathway. Overall, our results further emphasised the importance of cloning and sequencing independent transcripts to reveal less abundant, aberrant products, which often could not be detected by direct sequencing. Moreover, the different splicing patterns observed in the three patients as a consequence of point mutations show how sensitive the balance is between constitutive and cryptic splice sites in the IDS gene. The generation of such diverse transcripts, together with their level of expression, could contribute to the profound phenotypic variability reported in MPS II.
J Mol Med (Berl) 2006 Aug
PMID:Multiple cryptic splice sites can be activated by IDS point mutations generating misspliced transcripts. 1669 54


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