Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency

Mizumoto, Shuji; Kosho, Tomoki; Hatamochi, Atsushi; Honda, Tomoko; Yamaguchi, Tomomi; Okamoto, Nobuhiko; Miyake, Noriko; Yamada, Shuhei; Sugahara, Kazuyuki

doi:10.1016/j.clinbiochem.2017.02.018

Cited by 25 publications

(27 citation statements)

References 40 publications

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“…This makes GAGs key modulators in many diseases, giving them potential therapeutic applications. For example, heparan sulfate (HS) is released during sepsis and induces septic shock [18,19]; the removal of chondroitin sulfate (CS) may enhance memory retention and slow neurodegeneration in patients with Alzheimer's disease [20][21][22]; and dermatan enhance memory retention and slow neurodegeneration in patients with Alzheimer's disease [20][21][22]; and dermatan sulfate (DS) deficiency has been implicated in Ehlers-Danlos syndrome, thus the screening of DS in urine could be used as an early diagnostic tool [23,24].…”

Section: Introductionmentioning

confidence: 99%

Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data

et al. 2020

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Glycosaminoglycans (GAGs) are linear, structurally diverse, conformationally complex carbohydrate polymers that may contain up to 200 monosaccharides. These characteristics present a challenge for studying GAG conformational thermodynamics at atomic resolution using existing experimental methods. Molecular dynamics (MD) simulations can overcome this challenge but are only feasible for short GAG polymers. To address this problem, we developed an algorithm that applies all conformational parameters contributing to GAG backbone flexibility (i.e., bond lengths, bond angles, and dihedral angles) from unbiased all-atom explicit-solvent MD simulations of short GAG polymers to rapidly construct models of GAGs of arbitrary length. The algorithm was used to generate non-sulfated chondroitin 10- and 20-mer ensembles which were compared to MD-generated ensembles for internal validation. End-to-end distance distributions in constructed and MD-generated ensembles have minimal differences, suggesting that our algorithm produces conformational ensembles that mimic the backbone flexibility seen in simulation. Non-sulfated chondroitin 100- and 200-mer ensembles were constructed within a day, demonstrating the efficiency of the algorithm and reduction in time and computational cost compared to simulation.

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Section: Introductionmentioning

confidence: 99%

Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data

et al. 2020

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“…All of these functions allow GAGs to modulate disease. For example, hyaluronan can predict disease outcome and is used as a treatment for osteoarthritis [ 18 , 19 ]; deficiency of dermatan sulfate has been linked to Ehlers-Danlos syndrome, so screening of dermatan sulfate in urine may present a method of diagnosis [ 20 , 21 ]; reduced cerebral cell keratan sulfate levels have been implicated in Alzheimer’s disease [ 22 ]; and heparan sulfate has been shown to induce septic shock [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Constructing 3-Dimensional Atomic-Resolution Models of Nonsulfated Glycosaminoglycans with Arbitrary Lengths Using Conformations from Molecular Dynamics

Whitmore

Martin

Guvench

2020

IJMS

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Glycosaminoglycans (GAGs) are the linear carbohydrate components of proteoglycans (PGs) and are key mediators in the bioactivity of PGs in animal tissue. GAGs are heterogeneous, conformationally complex, and polydisperse, containing up to 200 monosaccharide units. These complexities make studying GAG conformation a challenge for existing experimental and computational methods. We previously described an algorithm we developed that applies conformational parameters (i.e., all bond lengths, bond angles, and dihedral angles) from molecular dynamics (MD) simulations of nonsulfated chondroitin GAG 20-mers to construct 3-D atomic-resolution models of nonsulfated chondroitin GAGs of arbitrary length. In the current study, we applied our algorithm to other GAGs, including hyaluronan and nonsulfated forms of dermatan, keratan, and heparan and expanded our database of MD-generated GAG conformations. Here, we show that individual glycosidic linkages and monosaccharide rings in 10- and 20-mers of hyaluronan and nonsulfated dermatan, keratan, and heparan behave randomly and independently in MD simulation and, therefore, using a database of MD-generated 20-mer conformations, that our algorithm can construct conformational ensembles of 10- and 20-mers of various GAG types that accurately represent the backbone flexibility seen in MD simulations. Furthermore, our algorithm efficiently constructs conformational ensembles of GAG 200-mers that we would reasonably expect from MD simulations.

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“…This result suggested a systemic depletion of DS in patients with mcEDS-CHST14; thus we presume that our urinary disaccharide analysis method can be implemented to allow a non-invasive screening for mcEDS-CHST14 [30]. established a urinary disaccharide analysis of CS/DS chains through an anion-exchange chromatography after treatment with DS-specific degrading enzymes; this analysis method showed that no DS was present in the urine of eight patients with mcEDS-CHST14 [30]. This result suggested a systemic depletion of DS in patients with mcEDS-CHST14; thus we presume that our urinary disaccharide analysis method can be implemented to allow a non-invasive screening for mcEDS-CHST14 [30].…”

Section: Glycobiological Findingsmentioning

confidence: 88%

“…Thus, impaired 4-O-sulfation inhibition due to D4ST1 deficiency enables back-epimerization from L-iduronic acid (IdoUA) to D-glucuronic acid (GlcUA) ( Figure 3E) [4,6,7]. In our laboratory, we have established a urinary disaccharide analysis of CS/DS chains through an anion-exchange chromatography after treatment with DS-specific degrading enzymes; this analysis method showed that no DS was present in the urine of eight patients with mcEDS-CHST14 [30]. This result suggested a systemic depletion of DS in patients with mcEDS-CHST14; thus we presume that our urinary disaccharide analysis method can be implemented to allow a non-invasive screening for mcEDS-CHST14 [30].…”

Section: Glycobiological Findingsmentioning

confidence: 99%

“…In our laboratory, we have established a urinary disaccharide analysis of CS/DS chains through an anion-exchange chromatography after treatment with DS-specific degrading enzymes; this analysis method showed that no DS was present in the urine of eight patients with mcEDS-CHST14 [30]. This result suggested a systemic depletion of DS in patients with mcEDS-CHST14; thus we presume that our urinary disaccharide analysis method can be implemented to allow a non-invasive screening for mcEDS-CHST14 [30]. established a urinary disaccharide analysis of CS/DS chains through an anion-exchange chromatography after treatment with DS-specific degrading enzymes; this analysis method showed that no DS was present in the urine of eight patients with mcEDS-CHST14 [30].…”

Section: Glycobiological Findingsmentioning

confidence: 99%

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Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

Kosho

Mizumoto

Watanabe

et al. 2019

Genes

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Musculocontractural Ehlers-Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE). Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous (Chst14 −/− ) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.

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Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency

Cited by 25 publications

References 40 publications

Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data

Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data

Constructing 3-Dimensional Atomic-Resolution Models of Nonsulfated Glycosaminoglycans with Arbitrary Lengths Using Conformations from Molecular Dynamics

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

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