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International Journal of Molecular... Sep 2022Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by genetic defects that result in deficiency of one specific enzyme activity, consequently impairing...
Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by genetic defects that result in deficiency of one specific enzyme activity, consequently impairing the stepwise degradation of glycosaminoglycans (GAGs). Except for MPS II, the other types of MPS have autosomal recessive inheritance in which two copies of an abnormal allele must be present in order for the disease to develop. In this study, we present the status of variant alleles and biochemistry results found in infants suspected of having MPS I, II, IVA, and VI. A total of 324 suspected infants, including 12 for MPS I, 223 for MPS II, 72 for MPS IVA, and 17 for MPS VI, who were referred for MPS confirmation from newborn screening centers in Taiwan, were enrolled. In all of these infants, one specific enzyme activity in dried blood spot filter paper was lower than the cut-off value in the first blood sample, as well asin a second follow-up sample. The confirmatory methods used in this study included Sanger sequencing, next-generation sequencing, leukocyte enzyme fluorometric assay, and GAG-derived disaccharides in urine using tandem mass spectrometry assays. The results showed that five, nine, and six infants had MPS I, II, and IVA, respectively, and all of them were asymptomatic. Thus, a laboratory diagnosis is extremely important to confirm the diagnosis of MPS. The other infants with identified nucleotide variations and reductions in leukocyte enzyme activities were categorized as being highly suspected cases requiring long-term and intensive follow-up examinations. In summary, the final confirmation of MPS depends on the most powerful biomarkers found in urine, i.e., the quantification of GAG-derived disaccharides including dermatan sulfate, heparan sulfate, and keratan sulfate, and analysis of genetic variants can help predict outcomes and guide treatment.
Topics: Disaccharides; Glycosaminoglycans; Humans; Infant; Infant, Newborn; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis II; Tandem Mass Spectrometry
PubMed: 36077388
DOI: 10.3390/ijms23179979 -
Nature Communications Aug 2022Glycosaminoglycans are highly anionic functional polysaccharides with information content in their structure that plays a major role in the communication between the...
Glycosaminoglycans are highly anionic functional polysaccharides with information content in their structure that plays a major role in the communication between the cell and the extracellular environment. The study presented here reports the label-free detection and analysis of glycosaminoglycan molecules at the single molecule level using sensing by biological nanopore, thus addressing the need to decipher structural information in oligo- and polysaccharide sequences, which remains a major challenge for glycoscience. We demonstrate that a wild-type aerolysin nanopore can detect and characterize glycosaminoglycan oligosaccharides with various sulfate patterns, osidic bonds and epimers of uronic acid residues. Size discrimination of tetra- to icosasaccharides from heparin, chondroitin sulfate and dermatan sulfate was investigated and we show that different contents and distributions of sulfate groups can be detected. Remarkably, differences in α/β anomerization and 1,4/1,3 osidic linkages can also be detected in heparosan and hyaluronic acid, as well as the subtle difference between the glucuronic/iduronic epimers in chondroitin and dermatan sulfate. Although, at this stage, discrimination of each of the constituent units of GAGs is not yet achieved at the single-molecule level, the resolution reached in this study is an essential step toward this ultimate goal.
Topics: Chondroitin Sulfates; Dermatan Sulfate; Glycosaminoglycans; Nanopores; Polysaccharides; Sulfates
PubMed: 36042212
DOI: 10.1038/s41467-022-32800-4 -
American Journal of Physiology. Cell... Dec 2022Proteoglycans consist of a core protein substituted with one or more glycosaminoglycan (GAG) chains and execute versatile functions during many physiological and... (Review)
Review
Proteoglycans consist of a core protein substituted with one or more glycosaminoglycan (GAG) chains and execute versatile functions during many physiological and pathological processes. The biosynthesis of GAG chains is a complex process that depends on the concerted action of a variety of enzymes. Central to the biosynthesis of heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS) GAG chains is the formation of a tetrasaccharide linker region followed by biosynthesis of HS or CS/DS-specific repeating disaccharide units, which then undergo modifications and epimerization. The importance of these biosynthetic enzymes is illustrated by several severe pleiotropic disorders that arise upon their deficiency. The Ehlers-Danlos syndromes (EDS) constitute a special group among these disorders. Although most EDS types are caused by defects in fibrillar types I, III, or V collagen, or their modifying enzymes, a few rare EDS types have recently been linked to defects in GAG biosynthesis. Spondylodysplastic EDS (spEDS) is caused by defective formation of the tetrasaccharide linker region, either due to β4GalT7 or β3GalT6 deficiency, whereas musculocontractural EDS (mcEDS) results from deficiency of D4ST1 or DS-epi1, impairing DS formation. This narrative review highlights the consequences of GAG deficiency in these specific EDS types, summarizes the associated phenotypic features and the molecular spectrum of reported pathogenic variants, and defines the current knowledge on the underlying pathophysiological mechanisms based on studies in patient-derived material, in vitro analyses, and animal models.
Topics: Animals; Dermatan Sulfate; Sulfotransferases; Ehlers-Danlos Syndrome; Collagen; Proteoglycans
PubMed: 35993517
DOI: 10.1152/ajpcell.00127.2022 -
European Review For Medical and... Jul 2022Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for...
OBJECTIVE
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.
PATIENTS AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 35916809
DOI: 10.26355/eurrev_202207_29300 -
Journal of Clinical Medicine Jul 2022Sulfated glycosaminoglycans (sGAGs) are likely to play an important role in the development and progression of rheumatoid arthritis (RA)-associated atherosclerosis. The...
TNF-α Inhibitors in Combination with MTX Reduce Circulating Levels of Heparan Sulfate/Heparin and Endothelial Dysfunction Biomarkers (sVCAM-1, MCP-1, MMP-9 and ADMA) in Women with Rheumatoid Arthritis.
Sulfated glycosaminoglycans (sGAGs) are likely to play an important role in the development and progression of rheumatoid arthritis (RA)-associated atherosclerosis. The present study investigated the effect of anti-tumor necrosis factor-α (anti-TNF-α) therapy in combination with methotrexate on plasma sGAG levels and serum markers of endothelial dysfunction. Among sGAG types, plasma chondroitin/dermatan sulfate (CS/DS) and heparan sulfate/heparin (HS/H) were characterized using electrophoretic fractionation. Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9) and asymmetric dimethylarginine (ADMA) were measured by immunoassays. The measurements were carried out four times: at baseline and after 3, 9 and 15 months of anti-TNF-α therapy. All analyzed parameters, excluding ADMA, were significantly elevated in patients with RA before the implementation of biological therapy compared to healthy subjects. Performed anti-TNF-α treatment led to a successive decrease in HS/H levels toward normal values, without any effect on CS/DS levels in female RA patients. The treatment was also effective at lowering the serum levels of sVCAM-1, MCP-1, MMP-9 and ADMA. Moreover, a significant positive correlation was found between the circulating HS/H and the 28 joint disease activity score based on the erythrocyte sedimentation rate (DAS28-ESR, r = 0.408; p <0.05), MCP-1 (r = 0.398; p <0.05) and ADMA (r = 0.396; p <0.05) in patients before the first dose of TNF-α inhibitor. In conclusion, a beneficial effect of anti-TNF-α therapy on cell-surface heparan sulfate proteoglycans (HSPGs)/HS turnover and endothelial dysfunction was observed in this study. This was manifested by a decrease in blood HS/H levels and markers of endothelial activation, respectively. Moreover, the decrease in the concentration of HS/H in the blood of patients during treatment, progressing with the decline in disease activity, indicates that the plasma HS/H profile may be useful for monitoring the efficacy of anti-TNF-α treatment in patients with RA.
PubMed: 35887981
DOI: 10.3390/jcm11144213 -
Journal of Molecular Medicine (Berlin,... Aug 2022Mucopolysaccharidosis type II (MPS II) is a neurometabolic disorder, due to the deficit of the lysosomal hydrolase iduronate 2-sulfatase (IDS). This leads to a severe...
Mucopolysaccharidosis type II (MPS II) is a neurometabolic disorder, due to the deficit of the lysosomal hydrolase iduronate 2-sulfatase (IDS). This leads to a severe clinical condition caused by a multi-organ accumulation of the glycosaminoglycans (GAGs/GAG) heparan- and dermatan-sulfate, whose elevated levels can be detected in body fluids. Since 2006, enzyme replacement therapy (ERT) has been clinically applied, showing efficacy in some peripheral districts. In addition to clinical monitoring, GAG dosage has been commonly used to evaluate ERT efficacy. However, a strict long-term monitoring of GAG content and composition in body fluids has been rarely performed. Here, we report the characterization of plasma and urine GAGs in Ids knock-out (Ids-ko) compared to wild-type (WT) mice, and their changes along a 24-week follow-up, with and without ERT. The concentration of heparan-sulfate (HS), chondroitin-sulfate (CS), and dermatan-sulfate (DS), and of the non-sulfated hyaluronic acid (HA), together with their differentially sulfated species, was quantified by capillary electrophoresis with laser-induced fluorescence. In untreated Ids-ko mice, HS and CS + DS were noticeably increased at all time points, while during ERT follow-up, a substantial decrease was evidenced for HS and, to a minor extent, for CS + DS. Moreover, several structural parameters were altered in untreated ko mice and reduced after ERT, however without reaching physiological values. Among these, disaccharide B and HS 2s disaccharide showed to be the most interesting candidates as biomarkers for MPS II. GAG chemical signature here defined provides potential biomarkers useful for an early diagnosis of MPS II, a more accurate follow-up of ERT, and efficacy evaluations of newly proposed therapies. KEY MESSAGES : Plasmatic and urinary GAGs are useful markers for MPS II early diagnosis and prognosis. CE-LIF allows GAG structural analysis and the quantification of 17 different disaccharides. Most GAG species increase and many structural features are altered in MPS II mouse model. GAG alterations tend to restore to wild-type levels following ERT administration. CS+DS/HS ratio, % 2,4dis CS+DS, and % HS 2s are potential markers for MPS II pathology and ERT efficacy.
Topics: Animals; Biomarkers; Body Fluids; Dermatan Sulfate; Disaccharides; Disease Models, Animal; Enzyme Replacement Therapy; Glycosaminoglycans; Heparitin Sulfate; Mice; Mice, Knockout; Mucopolysaccharidosis II
PubMed: 35816218
DOI: 10.1007/s00109-022-02221-3 -
International Journal of Molecular... Jul 2022The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular... (Review)
Review
The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers-Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade.
Topics: Animals; Collagen; Dermatan Sulfate; Ehlers-Danlos Syndrome; Female; Glycosaminoglycans; Mice; Mice, Knockout; Pregnancy; Sulfotransferases
PubMed: 35806490
DOI: 10.3390/ijms23137485 -
Molecular Genetics and Metabolism... Jun 2022Mucopolysaccharidosis type II (MPS II) is a multisystemic lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase enzyme. Currently, enzyme...
Mucopolysaccharidosis type II (MPS II) is a multisystemic lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase enzyme. Currently, enzyme replacement therapy (ERT) with recombinant idursulfase is the main treatment available to decrease morbidity and improve quality of life. However, infusion-associated reactions (IARs) are reported and may limit access to treatment. When premedication or infusion rate reductions are ineffective for preventing IARs, desensitization can be applied. To date, only two MPS II patients are reported to have undergone desensitization. We report a pediatric patient with recurrent IARs during infusion successfully managed with gradual desensitization. Our protocol started at 50% of the standard dosage infused at concentrations from 0.0006 to 0.06 mg/ml on weeks 1 and 2, followed by 75% of the standard dosage infused at concentrations from 0.0009 to 0.09 mg/ml on weeks 3 and 4, and full standard dosage thereafter, infused at progressively increasing concentrations until the standard infusion conditions were reached at 3 months. Our experience can be used in the management of MPS II patients presenting IARs to idursulfase infusion, even when general preventive measures are already administered.
PubMed: 35782619
DOI: 10.1016/j.ymgmr.2022.100878 -
Stem Cell Research Aug 2022Mucopolysaccharidosis type II (Hunter Syndrome) is a rare X-linked inherited lysosomal storage disorder presenting a wide genetic heterogeneity. It is due to pathogenic...
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
PubMed: 35759972
DOI: 10.1016/j.scr.2022.102846 -
Frontiers in Cell and Developmental... 2022
PubMed: 35757004
DOI: 10.3389/fcell.2022.941178