iduronate and Mucopolysaccharidosis-II

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.

Topics: Child; Enzyme Replacement Therapy; Glycosaminoglycans; Humans; Iduronate Sulfatase; Iduronic Acid; Infant, Newborn; Mucopolysaccharidosis II; Neonatal Screening; United States

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder characterized by an accumulation of glycosaminoglycans (GAGs), including heparan sulfate, in the body. Major manifestations involve the central nerve system (CNS), skeletal deformation, and visceral manifestations. About 30% of MPS II is linked with an attenuated type of disease subtype with visceral involvement. In contrast, 70% of MPS II is associated with a severe type of disease subtype with CNS manifestations that are caused by the human iduronate-2-sulfatase (IDS)-Pro86Leu (P86L) mutation, a common missense mutation in MPS II. In this study, we reported a novel Ids-P88L MPS II mouse model, an analogous mutation to human IDS-P86L. In this mouse model, a significant impairment of IDS enzyme activity in the blood with a short lifespan was observed. Consistently, the IDS enzyme activity of the body, as assessed in the liver, kidney, spleen, lung, and heart, was significantly impaired. Conversely, the level of GAG was elevated in the body. A putative biomarker with unestablished nature termed UA-HNAc(1S) (late retention time), one of two UA-HNAc(1S) species with late retention time on reversed-phase separation,is a recently reported MPS II-specific biomarker derived from heparan sulfate with uncharacterized mechanism. Thus, we asked whether this biomarker might be elevated in our mouse model. We found a significant accumulation of this biomarker in the liver, suggesting that hepatic formation could be predominant. Finally, to examine whether gene therapy could enhance IDS enzyme activity in this model, the efficacy of the nuclease-mediated genome correction system was tested. We found a marginal elevation of IDS enzyme activity in the treated group, raising the possibility that the effect of gene correction could be assessed in this mouse model. In conclusion, we established a novel Ids-P88L MPS II mouse model that consistently recapitulates the previously reported phenotype in several mouse models.

Topics: Animals; Biomarkers; Disease Models, Animal; Heparitin Sulfate; Humans; Iduronate Sulfatase; Iduronic Acid; Mice; Mucopolysaccharidosis II; Mutation

Mucopolysaccharidosis type II, commonly called Hunter syndrome, is a rare X-linked recessive disease caused by the deficiency of the lysosomal enzyme iduronate-2-sulphatase (I2S). A deficiency of I2S causes an abnormal glycosaminoglycans accumulation in the body's cells. Although enzyme replacement therapy is the standard therapy, adeno-associated viruses (AAV)-based gene therapy could provide a single-dose solution to achieve a prolonged and constant enzyme level to improve patient's quality of life. Currently, there is no integrated regulatory guidance to describe the bioanalytical assay strategy to support gene therapy products. Herein, we describe the streamlined strategy to validate/qualify the transgene protein and its enzymatic activity assays. The method validation for the I2S quantification in serum and method qualification in tissues was performed to support the mouse GLP toxicological study. Standard curves for I2S quantification ranged from 2.00 to 50.0 μg/mL in serum and 6.25 to 400 ng/mL in the surrogate matrix. Acceptable precision, accuracy, and parallelism in the tissues were demonstrated. To assess the function of the transgene protein, fit-for-purpose method qualification for the I2S enzyme activity in serum was performed. The observed data indicated that the enzymatic activity in serum increased dose-dependently in the lower I2S concentration range. The highest I2S transgene protein was observed in the liver among tissue measured, and its expression level was maintained up to 91 days after the administration of rAAV8 with a codon-optimized human I2S. In conclusion, the multifaceted bioanalytical method for I2S and its enzymatic activity were established to assess gene therapy products in Hunter syndrome.

Topics: Animals; Enzyme Replacement Therapy; Genetic Therapy; Humans; Iduronate Sulfatase; Iduronic Acid; Mice; Mucopolysaccharidosis II; Quality of Life

Multiple complex intracellular cascades contributing to Hunter syndrome (mucopolysaccharidosis type II) pathogenesis have been recognized and documented in the past years. However, the hierarchy of early cellular abnormalities leading to irreversible neuronal damage is far from being completely understood. To tackle this issue, we have generated two novel iduronate-2-sulfatase (IDS) loss of function human neuronal cell lines by means of genome editing. We show that both neuronal cell lines exhibit no enzymatic activity and increased GAG storage despite a completely different genotype. At a cellular level, they display reduced differentiation, significantly decreased LAMP1 and RAB7 protein levels, impaired lysosomal acidification and increased lipid storage. Moreover, one of the two clones is characterized by a marked decrease of the autophagic marker p62, while none of the two mutants exhibit marked oxidative stress and mitochondrial morphological changes. Based on our preliminary findings, we hypothesize that neuronal differentiation might be significantly affected by IDS functional impairment.

Topics: Cell Line; CRISPR-Cas Systems; Humans; Iduronate Sulfatase; Iduronic Acid; Mucopolysaccharidosis II

Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.

Topics: Animals; Blood-Retinal Barrier; Glycosaminoglycans; Iduronate Sulfatase; Iduronic Acid; Mice; Mucopolysaccharidosis II; Receptors, Transferrin; Retinal Diseases

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare X-linked inherited lysosomal storage disorder presenting a wide genetic heterogeneity. It is due to pathogenic variants in the IDS gene, causing the deficit of the lysosomal hydrolase iduronate 2-sulfatase, degrading the glycosaminoglycans (GAGs) heparan- and dermatan-sulfate. Based on the presence/absence of neurocognitive signs, commonly two forms are recognized, the severe and the attenuate ones. Here we describe a line of induced pluripotent stem cells, generated from dermal fibroblasts, carrying the mutation c.479C>T, and obtained from a patient showing an attenuated phenotype. The line will be useful to study the disease neuropathogenesis.

Topics: Glycosaminoglycans; Humans; Iduronate Sulfatase; Iduronic Acid; Induced Pluripotent Stem Cells; Mucopolysaccharidosis II; Phenotype

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for degrading heparan and dermatan sulfate. The IDS gene is located on chromosome Xq28; pathological variants in this gene mostly consist of missense mutations and small and larger deletions, which produce different phenotypes. However, there is only one record in our population concerning the molecular mechanism of this disease; a genotype-phenotype description is not available.. There were included 24 unrelated male patients; clinical features were recorded at a database, fluorometric IDS enzyme activity testing was done for each individual, followed by Sanger sequencing to identify mutations.. The mutational spectrum was found in 16 out of 24 Mexican patients with MPS II, and its range of phenotypes was described. The most frequent variants were of the missense type. The most affected exons were exon 3 (c.275T>G, c.284_287del, c.325T>C), exon 8 (c.1035G>C, c.550G>A), exon 9 (c.1403G>C, c.1229_1229del), and exon 7 (c.979A>C; this variant has not been previously reported). Exon 5 (c.438C>T, a non-pathogenic variant) was the least frequent. It was also found that the most severely affected patients were those with large deletions (2 out of 24) [rsaIDS: IDSP1 (P164)x0, FMR1, AFF2 (P164)x2] involving genes and pseudogenes. We found 2 patients with a synonymous mutation in exon 4.. Our results confirmed reports in the literature, since the most frequent variants were reported in exons 3 and 8. However, this result varies from one previous report in our population, which mentions large deletions and rearrangements as the most frequent alterations, since complex rearrangements were not found. According to what has been previously found, the most severely affected patients are those in which a whole gene has been deleted.

Topics: Fragile X Mental Retardation Protein; Humans; Iduronate Sulfatase; Iduronic Acid; Male; Mucopolysaccharidosis II; Mutation; Phenotype

The Sendai virus vector has received a lot of attention due to its broad tropism for mammalian cells. As a result of efforts for genetic studies based on a mutant virus, we can now express more than 10 genes of up to 13.5 kilo nucleotides in a single vector with high protein expression efficiency. To prove this benefit, we examined the efficacy of the novel ribonucleic acid (RNA) virus vector harboring the human iduronate-2-sulfatase (IDS) gene with 1,653 base pairs, a causative gene for mucopolysaccharidosis type II, also known as a disorder of lysosomal storage disorders. As expected, this novel RNA vector with the human IDS gene exhibited its marked expression as determined by the expression of enhanced green fluorescent protein and IDS enzyme activity. While these cells exhibited a normal growth rate, the BHK-21 transformant cells stably expressing the human IDS gene persistently generated an active human IDS enzyme extracellularly. The human IDS protein produced failed to be incorporated into the lysosome when cells were pretreated with mannose-6-phosphate, demonstrating that this human IDS enzyme has potential for therapeutic use by cross-correction. These results suggest that our novel RNA vector may be applicable for further clinical settings.

Topics: Animals; Humans; Iduronate Sulfatase; Iduronic Acid; Lysosomes; Mucopolysaccharidosis II; RNA Viruses

To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois.. Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago.. One case of MPS II and 14 infants with pseudodeficiency for I2S were identified.. Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois.

Topics: Biomarkers; Dried Blood Spot Testing; Follow-Up Studies; Humans; Iduronic Acid; Illinois; Incidence; Infant, Newborn; Mucopolysaccharidosis II; Neonatal Screening; Reproducibility of Results; Retrospective Studies; Tandem Mass Spectrometry; Time Factors

Small molecules called pharmacological chaperones have been shown to improve the stability, intracellular localization, and function of mutated enzymes in several lysosomal storage diseases, and proposed as promising therapeutic agents for them. However, a chaperone compound for mucopolysaccharidosis type II (MPS II), which is an X-linked lysosomal storage disorder characterized by a deficiency of iduronate-2-sulfatase (IDS) and the accumulation of glycosaminoglycans (GAGs), has still not been developed. Here we focused on the Δ-unsaturated 2-sulfouronic acid-N-sulfoglucosamine (D2S0), which is a sulfated disaccharide derived from heparin, as a candidate compound for a pharmacological chaperone for MPS II, and analyzed the chaperone effect of the saccharide on IDS by using recombinant protein and cells expressing mutated enzyme. When D2S0 was incubated with recombinant human IDS (rhIDS) in vitro, the disaccharide attenuated the thermal degeneration of the enzyme. This effect of D2S0 on the thermal degeneration of rhIDS was enhanced in a dose-dependent manner. D2S0 also increased the residual activity of mutant IDS in patient fibroblasts. Furthermore, D2S0 improved the enzyme activity of IDS mutants derived from six out of seven different mutations in HEK293T cells transiently expressing them. These results indicate that D2S0 is a potential pharmacological chaperone for MPS II.

Topics: Disaccharides; Fibroblasts; Gene Expression Regulation, Enzymologic; Glycosaminoglycans; HEK293 Cells; Heparin; Humans; Iduronate Sulfatase; Iduronic Acid; Molecular Chaperones; Mucopolysaccharidosis II; Mutation; Skin; Sulfates

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease-specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice.

Topics: Animals; Biomarkers; Cerebrum; Enzyme Replacement Therapy; Female; Glycosaminoglycans; Humans; Iduronate Sulfatase; Iduronic Acid; Iduronidase; Liver; Mice, Inbred C57BL; Mucopolysaccharidosis II

We devised iduronate-2-sulfatase (IDS) enzyme activity assays by combining fluorometric substrate and LC-MS/MS based detection.. 4-Methylumbelliferyl α-L-idopyranosiduronic acid 2-sulfate (IDS-S) was used as a substrate for IDS. Its enzymatic product, 4-methylumbelliferyl α-L-idopyranosiduronic acid (IDS-P) and internal standard, 4-methylumbelliferyl α-L-idopyranoside (IDS-IS), were directly measured by UPLC-MS/MS. We determined the precision of our enzyme assay and the effects of sample amounts and incubation time based on the results. Dried blood spots (DBSs) of 110 normal newborns and three patients with Hunter disease were analyzed.. IDS-IS, IDS-P and IDS-S were fully separated using UPLC without any ion suppressions. The intra- and inter-assay precisions were 8.5-10.5% and 11.9-15.3%, respectively. The amount of product obtained was proportional to the number of DBSs and increased linearly with the incubation period from 0 to 15 h. The enzyme activities in DBSs from three patients with MPS II were markedly lower than those in the DBSs of 110 normal newborns.. To the best of our knowledge, this is the first report describing the use of LC-MS/MS for the diagnosis of Hunter disease with a commercially available substrate. Our method would be a rapid and effective screening tool for the diagnosis of Hunter disease with further study.

Topics: Biological Assay; Biomarkers; Chromatography, High Pressure Liquid; Dried Blood Spot Testing; Gene Expression; Glycoproteins; Humans; Iduronic Acid; Infant, Newborn; Methylglycosides; Mucopolysaccharidosis II; Neonatal Screening; Tandem Mass Spectrometry

The present study aimed to characterize mutant alleles in Mucopolysaccharidosis II and evaluate possible reduction of mRNA amount consequent to nonsense-mediated or nonstop mRNA decay pathways. A combination of different approaches, including real-time RT-PCR, were used to molecularly characterize seventeen patients. Fifteen alleles were identified and nine of them were new. The novel alleles consisted of three missense mutations (p.S71R, p.P197R, p.C432R), two nonsense (p.Q66X, p.L359X), two frameshifts (p.V136fs75X, p.C432fs8X), one allele carrying two in-cis mutations [p.D252N;p.S369X], and a large deletion (p.G394_X551). Analysing these results it emerged that most of the alterations resulted in mutants leading to mRNAs with premature termination codons, and therefore, potentially sensitive to mRNA surveillance pathway. By using real-time RT-PCR, the mRNAs resulting (i) from substitutions that changed one amino acid to a stop codon (L359X, and S369X), or caused the shifted reading frame with premature introduction of a stop codon (C432fs8X), (ii) from large deletion (p.G394_X551) that included the termination codon, seemed to be subject to degradation by nonsense-mediated (i) or nonstop decay (ii) mechanisms, as mRNA was strongly underexpressed. On the contrary, two mutations (Q66X and V136fs75X) produced transcripts evading mRNA surveillance pathway despite both of them fulfilled the known criteria. These results confirm the wide variability of the mRNA expression levels previously reported and represent a further exception to the rules governing susceptibility to nonsense-mediated decay. A close examination of the molecular basis of the disease is becoming increasingly important for optimising the choices of available or forthcoming therapies such as, enzyme replacement therapy or enzyme enhancement therapy.

Topics: Alleles; Cells, Cultured; Child; Child, Preschool; Codon, Nonsense; Codon, Terminator; Frameshift Mutation; Genotype; Humans; Iduronic Acid; Infant; Mucopolysaccharidosis II; Mutation, Missense; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; RNA Stability; RNA, Messenger; Sequence Deletion

Mucopolysaccharidosis type II (MPS II, Hunter syndrome, OMIM 309900) is an X-linked recessive lysosomal storage disease resulting from a deficiency of iduronte-2-sulphate sulphatase (IDS). The present study aimed to establish an enzyme assay method for IDS activity for carrying out postnatal and prenatal diagnosis of MPS II by means of IDS activity assay on plasma, uncultured chorionic villi (CV) and cultured amniotic fluid cells (AF cell) using a new synthesized substrate.. A fluorigenic substrate (4-methylumbelliferyl-alpha-iduronate-2-sulphate, MU-alpha-Idu-2S) was used for the assay of IDS activity. IDS activity in plasma was determined for diagnosis of the proband. Prenatal diagnosis in 10 pregnancies at risk was carried out according to IDS activity on uncultured CV at 11th week or on cultured AF cell at 18th week of gestation. At the same time, IDS activity was also determined in the maternal plasmas to observe the change of IDS activity in pregnancy. The fetal sex determination was performed by PCR amplification of the ZFX/ZFY genes.. The IDS activity in plasma of normal controls and obligate heterozygotes were 240.2 - 668.2 nmol/(4 hxml) and 88.7 - 547.9 nmol/(4 hxml), respectively, while the enzyme activities in plasmas were in the range of 0.3 - 18.6 nmol/(4 hxml) in affected male. The IDS activities were 37.2 - 54.9 nmol/(4 hxmg protein) and 21.4 - 74.4 nmol/(4 hxmg protein) in CV and cultured AF cells respectively. Out of 50 suspected cases, 46 were diagnosed as having MPS II and 4 were excluded. Prenatal diagnosis was performed on 10 pregnancies at risk. Four of 5 male fetuses [IDS activity were 4.7, 1.8, 7.0 nmol/(4hxmg protein) in CV, 0.6 nmol/(4 hxmg protein) in AF cell] were diagnosed as having MPS II and the other 5 fetuses were normal females [IDS activity were: 48.7, 5.9, 25.2 nmol/(4 hxmg protein) in CV, 55.2, 40.9 nmol/(4 hxmg protein) in AF cell]. Increased IDS activity was observed in plasma of the pregnant women with unaffected fetuses, while the IDS activity decreased in pregnancies with affected fetuses. IDS activity of one female fetus was very low [5.9 nmol/(4 hxmg protein)], but the IDS activity in maternal plasmas increased, this fetus was a normal female.. The method using a synthesized fluorigenic 4-methylumbelliferyl-substrate was a sensitive, rapid and convenient assay of IDS activity and was reliable for early prenatal diagnosis. Determination of fetal sex would be helpful in excluding the female fetus with low IDS activity from being considered as an affected male fetus. It would be further helpful if IDS activity in maternal plasma was taken into account.

Topics: Amniotic Fluid; Cells, Cultured; Child; Child, Preschool; China; Chorionic Villi; Chorionic Villi Sampling; Enzyme Assays; Female; Fetus; Fluorometry; Heterozygote; Humans; Hymecromone; Iduronate Sulfatase; Iduronic Acid; Karyotyping; Male; Mucopolysaccharidosis II; Polymerase Chain Reaction; Pregnancy; Pregnancy, High-Risk; Prenatal Diagnosis; Reference Values; Sex Factors

4-Methylumbelliferyl-alpha-iduronate 2-sulphate was synthesized and shown to be a specific substrate for the lysosomal iduronate-2-sulphate sulphatase (IDS). Fibroblasts (n = 17), leukocytes (n = 3) and plasmas (n = 9) from different MPS II patients showed < 5% of mean normal IDS activity. The enzymatic liberation of the fluorochrome from 4-methylumbelliferyl-alpha-iduronate 2-sulphate requires the sequential action of IDS and alpha-iduronidase. A normal level of alpha-iduronidase activity was insufficient to complete the hydrolysis of the reaction intermediate 4-methylumbelliferyl-alpha-iduronide formed by IDS. A second incubation step in the presence of excess purified alpha-iduronidase is needed to avoid underestimation of the IDS activity.

Topics: Fibroblasts; Fluorometry; Humans; Hydrogen-Ion Concentration; Hymecromone; Iduronate Sulfatase; Iduronic Acid; Leukocytes; Lysosomes; Mucopolysaccharidosis II; Substrate Specificity

The iduronate-2-sulfatase (IDS) is a lysosomal enzyme that acts on sulphate groups on C-2 positions of the iduronic acid residues of the mucopolysaccharides heparan sulphate and dermatan sulphate. Recently, we described in mouse two IDS mRNAs: the first or canonic (MTA16), highly homologous to the human counterpart, the second or novel (MTA13), completely divergent from the canonic in the 3' region. In this study, by reverse transcriptase polymerase chain reaction (RT-PCR) we analyzed the expression of the two mRNA transcripts for the IDS gene in murine tissues, in various human cell-lines and in cells from some Hunter patients.

Topics: Animals; Base Sequence; Cell Line, Transformed; DNA Primers; Gene Expression; Humans; Iduronate Sulfatase; Iduronic Acid; Mice; Molecular Sequence Data; Mucopolysaccharidosis II; Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Some structural features of heparitin sulfate excreted by patients with Hunter syndrome are described. It is shown, with the aid of heparitinases and heparinase from Flavobacterium heparinum, that the Hunter heparitin sulfate is a very complex structure composed of nine different disaccharide units containing regions akin to normal heparitin sulfate and regions akin the heparin. Two-thirds of the iduronic acid residues of Hunter heparitin sulfate are devoid of sulfate, contrasting with heparin in which most of the iduronic acid residues are sulfated. The isolation and characterization of the non-reducing ends of heparin and of the heparitin sulfates is also described. Based on these results the specificity of the heparinase and heparitinases as well as the biosynthesis of iduronic acid-containing heparin-like compounds is discussed.

Topics: Chemical Phenomena; Chemistry; Disaccharides; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Iduronic Acid; Mucopolysaccharidosis II; Sulfates

Skin fibroblasts cultured from patients affected with the Hunter syndrome are deficient in the activity of a protein, named the "Hunter corrective factor," that is required for degradation of dermatan and heparan sulfates. We now show that this factor, purified from human urine, removes about 2% of the sulfate residues from [(35)S]mucopolysaccharide accumulated within Hunter fibroblasts; these groups are derived from "oversulfated" regions of the polymer. Acetone-powder extracts of fibroblasts derived from patients with the Hunter syndrome are deficient in this sulfatase, in contrast to similar extracts from fibroblasts of individuals of other genotype. Hunter corrective factor coupled to alpha-L-iduronidase (or alternatively, mixed extracts from Hurler and Hunter fibroblasts) release iduronic acid from 4-O-alpha-L-sulfoiduronosyl-D-sulfoanhydromannose. We conclude that the Hunter corrective factor is a sulfatase for sulfated iduronic acid residues.

Topics: Carbohydrate Metabolism, Inborn Errors; Cells, Cultured; Fibroblasts; Galactose; Glucosamine; Glucuronidase; Glycosaminoglycans; Glycosides; Humans; Iduronic Acid; Intellectual Disability; Mannose; Mucopolysaccharidosis II; Retinitis Pigmentosa; Skin; Sulfatases; Sulfur Isotopes; Sulfuric Acids; Tritium; Uronic Acids