-
Cureus Apr 2023Hurler syndrome is a rare autosomal recessive disorder of deficiency in the metabolism of glycosaminoglycans (GAGs), including heparan sulfate and dermatan sulfate,...
Hurler syndrome is a rare autosomal recessive disorder of deficiency in the metabolism of glycosaminoglycans (GAGs), including heparan sulfate and dermatan sulfate, which consequently accumulate in the different organs of the body, resulting from deficiency of an enzyme named Alpha-L-iduronidase. Here, we present an interesting case of a young female patient who presented with a combination of skeletal, oro-facial, ophthalmologic, neurological, and radiological findings of this disease. A diagnosis of Hurler syndrome (Mucopolysaccharidosis Type I) was made late in the disease due to lack of facilities, and the patient was ultimately managed supportively.
PubMed: 37213966
DOI: 10.7759/cureus.37785 -
Human Gene Therapy Apr 2024Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a mutation in the gene, resulting in deficiency of the enzyme iduronate-2-sulfatase...
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a mutation in the gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously delivered IDS is unable to cross the blood-brain barrier (BBB). Hematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (rabies virus glycoprotein [RVG] and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via hematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared with LV.IDS.ApoEII and LV.IDS in MPS II mice at 6 months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG- and LV.IDS.gh625-treated mice than in LV.IDS.ApoEII- and LV.IDS-treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis, and lysosomal swelling were partially normalized in MPS II mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalized by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared with control tissue from LV.IDS- and LV.IDS.ApoEII-transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPS II and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPS II disease than IDS alone.
Topics: Mice; Animals; Mucopolysaccharidosis II; Iduronic Acid; Rabies virus; Iduronate Sulfatase; Glycoproteins; Nervous System Diseases; Peptides
PubMed: 37212263
DOI: 10.1089/hum.2023.025 -
Therapeutic Advances in Rare Disease 2023Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficient levels and/or activity of glycosaminoglycan (GAG)-degradative...
Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by deficient levels and/or activity of glycosaminoglycan (GAG)-degradative enzymes. MPS are characterized by accumulation of the mucopolysaccharides heparan sulfate, dermatan sulfate, keratan sulfate, or chondroitin sulfate in tissues. We report the case of a 38-year-old woman with a history of joint restriction and retinitis pigmentosa who developed bivalvular heart failure requiring surgery. It was not until pathological examination of surgically excised valvular tissue that a diagnosis of MPS I was made. Her musculoskeletal and ophthalmologic symptoms, when placed in the context of MPS I, painted the diagnostic picture of a genetic syndrome that was overlooked until a diagnosis was made in late middle age.
PubMed: 37181073
DOI: 10.1177/26330040221145945 -
Data in Brief Jun 2023The data shown in this article are related to the published paper entitled "A novel 4--endosulfatase with high potential for the structure-function studies of...
The data shown in this article are related to the published paper entitled "A novel 4--endosulfatase with high potential for the structure-function studies of chondroitin sulfate/dermatan sulfate" in . In this article, the phylogenetic analysis, cloning, expression, purification, specificity and biochemical characteristics of the identified chondroitin sulfate/dermatan sulfate 4--endosulfatase (endoBI4SF) are described in detail. The recombinant endoBI4SF with a molecular mass of 59.13 kDa can can specifically hydrolyze the 4-- but not 2-- and 6--sulfate groups in the oligo-/polysaccharides of chondroitin sulfate/dermatan sulfate and show the maximum reaction rate in 50 mM Tris-HCl buffer (pH 7.0) at 50°C, which can be a very useful tool for the structural and functional studies of chondroitin sulfate/dermatan sulfate.
PubMed: 37113498
DOI: 10.1016/j.dib.2023.109139 -
Marine Drugs Mar 2023Crude anionic polysaccharides extracted from the Pacific starfish were purified by anion-exchange chromatography. The main fraction having MW 14.5 kDa and dispersity...
Crude anionic polysaccharides extracted from the Pacific starfish were purified by anion-exchange chromatography. The main fraction having MW 14.5 kDa and dispersity 1.28 (data of gel-permeation chromatography), was solvolytically desulfated and giving rise to preparation with a structure of dermatan core [→3)-β-d-GalNAc-(1→4)-α-l-IdoA-(1→], which was identified according to NMR spectroscopy data. Analysis of the NMR spectra of the parent fraction led to identification of the main component as dermatan sulfate →3)-β-d-GalNAc4R-(1→4)-α-l-IdoA2R3S-(1→ (where R was SO or H), bearing sulfate groups at O-3 or both at O-2 and O-3 of α-l-iduronic acid, as well as at O-4 of some N-acetyl-d-galactosamine residues. The minor signals in NMR spectra of were assigned as resonances of heparinoid composed of the fragments →4)-α-d-GlcNS3S6S-(1→4)-α-l-IdoA2S3S-(1→. The 3-O-sulfated and 2,3-di-O-sulfated iduronic acid residues are very unusual for natural glycosaminoglycans, and further studies are needed to elucidate their possible specific influence on the biological activity of the corresponding polysaccharides. To confirm the presence of these units in and , a series of variously sulfated model 3-aminopropyl iduronosides were synthesized and their NMR spectra were compared with those of the polysaccharides. Preparations and were studied as stimulators of hematopoiesis in vitro. Surprisingly, it was found that both preparations were active in these tests, and hence, the high level of sulfation is not necessary for hematopoiesis stimulation in this particular case.
Topics: Animals; Glycosaminoglycans; Dermatan Sulfate; Iduronic Acid; Starfish; Polysaccharides; Sulfates
PubMed: 37103344
DOI: 10.3390/md21040205 -
Thrombosis and Haemostasis Sep 2023Danaparoid sodium is a biopolymeric complex drug composed of the most abundant heparan sulfate (HS) followed in descending order by dermatan sulfate (DS) and...
OBJECTIVE
Danaparoid sodium is a biopolymeric complex drug composed of the most abundant heparan sulfate (HS) followed in descending order by dermatan sulfate (DS) and chondroitin sulfate (CS). This composite nature explains its peculiar antithrombotic and anticoagulant properties and make it particularly advantageous when the risk of heparin-induced thrombocytopenia occurs. A specific control of the danaparoid composition is required by the Ph. Eur. The monograph includes the CS and DS limit contents and describes the method for their quantification through selective enzymatic degradations.
MATERIALS AND METHODS
In this study, a quantitative two-dimensional nuclear magnetic resonance (NMR) method is proposed as a new method suitable for CS and DS quantification. Statistical comparison of the results provided by the analysis of a series of danaparoid samples with both NMR and enzymatic methods highlights a small systematic difference, likely derived from lyase-resistant sequences bearing oxidized terminals. Some modified structures, whose survival to the enzymatic action was confirmed by mass spectrometry, can be detected and quantified by NMR.
CONCLUSION AND RESULTS
The proposed NMR method can serve for the determination of DS and CS contents, is an easy-to-apply method with no dependence from enzymes and standards, and provides extensive structural information on the overall glycosaminoglycans mixture.
Topics: Humans; Dermatan Sulfate; Chondroitin Sulfates; Carbon Isotopes; Heparitin Sulfate; Magnetic Resonance Spectroscopy
PubMed: 37094794
DOI: 10.1055/s-0043-1768225 -
BioRxiv : the Preprint Server For... Apr 2023Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's Disease (AD), and the impact of modified chondroitin sulfates is being...
INTRODUCTION
Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's Disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI.
METHODS
Reports about chondroitin sulfate, chondroitin sulfate proteoglycans and chondroitin sulfatases in Alzheimer's Disease were reviewed. Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4, and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays.
RESULTS
SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate and i-NOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified.
DISCUSSION
Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse.
CONCLUSIONS
Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD.
PubMed: 37066366
DOI: 10.1101/2023.04.03.535377 -
PloS One 2023SLC35A3 is considered an uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter in mammals and regulates the branching of N-glycans. A missense mutation in...
SLC35A3 is considered an uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter in mammals and regulates the branching of N-glycans. A missense mutation in SLC35A3 causes complex vertebral malformation (CVM) in cattle. However, the biological functions of SLC35A3 have not been fully clarified. To address these issues, we have established Slc35a3-/-mice using CRISPR/Cas9 genome editing system. The generated mutant mice were perinatal lethal and exhibited chondrodysplasia recapitulating CVM-like vertebral anomalies. During embryogenesis, Slc35a3 mRNA was expressed in the presomitic mesoderm of wild-type mice, suggesting that SLC35A3 transports UDP-GlcNAc used for the sugar modification that is essential for somite formation. In the growth plate cartilage of Slc35a3-/-embryos, extracellular space was drastically reduced, and many flat proliferative chondrocytes were reshaped. Proliferation, apoptosis and differentiation were not affected in the chondrocytes of Slc35a3-/-mice, suggesting that the chondrodysplasia phenotypes were mainly caused by the abnormal extracellular matrix quality. Because these histological abnormalities were similar to those observed in several mutant mice accompanying the impaired glycosaminoglycan (GAG) biosynthesis, GAG levels were measured in the spine and limbs of Slc35a3-/-mice using disaccharide composition analysis. Compared with control mice, the amounts of heparan sulfate, keratan sulfate, and chondroitin sulfate/dermatan sulfate, were significantly decreased in Slc35a3-/-mice. These findings suggest that SLC35A3 regulates GAG biosynthesis and the chondrodysplasia phenotypes were partially caused by the decreased GAG synthesis. Hence, Slc35a3-/- mice would be a useful model for investigating the in vivo roles of SLC35A3 and the pathological mechanisms of SLC35A3-associated diseases.
Topics: Animals; Cattle; Mice; Biological Transport; Keratan Sulfate; Mammals; Musculoskeletal Abnormalities; Nucleotides; Osteochondrodysplasias; Uridine Diphosphate
PubMed: 37053259
DOI: 10.1371/journal.pone.0284292 -
The Journal of Biological Chemistry May 2023Chondroitinase ABC-type I (CSase ABC I), which can digest both chondroitin sulfate (CS) and dermatan sulfate (DS) in an endolytic manner, is an essential tool in...
Chondroitinase ABC-type I (CSase ABC I), which can digest both chondroitin sulfate (CS) and dermatan sulfate (DS) in an endolytic manner, is an essential tool in structural and functional studies of CS/DS. Although a few CSase ABC I have been identified from bacteria, the substrate-degrading pattern and regulatory mechanisms of them have rarely been investigated. Herein, two CSase ABC I, IM3796 and IM1634, were identified from the intestinal metagenome of CS-fed mice. They show high sequence homology (query coverage: 88.00%, percent identity: 90.10%) except for an extra peptide (Met-His) at the N-terminus in IM1634, but their enzymatic properties are very different. IM3796 prefers to degrade 6-O-sulfated GalNAc residue-enriched CS into tetra- and disaccharides. In contrast, IM1634 exhibits nearly a thousand times more activity than IM3796 and can completely digest CS/DS with various sulfation patterns to produce disaccharides, unlike most CSase ABC I. Structure modeling showed that IM3796 did not contain an N-terminal domain composed of two β-sheets, which is found in IM1634 and other CSase ABC I. Furthermore, deletion of the N-terminal domain (Met-His) from IM1634 caused the enzymatic properties of the variant IM1634-T109 to be similar to those of IM3796, and conversely, grafting this domain to IM3796 increased the similarity of the variant IM3796-A109 to IM1634. In conclusion, the comparative study of the new CSase ABC I provides two unique tools for CS/DS-related studies and applications and, more importantly, reveals the critical role of the N-terminal domain in regulating the substrate binding and degradation of these enzymes.
Topics: Animals; Mice; Bacteria; Chondroitin ABC Lyase; Chondroitin Sulfates; Dermatan Sulfate; Disaccharides; Peptides; Substrate Specificity
PubMed: 37031818
DOI: 10.1016/j.jbc.2023.104692