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Start Over Descriptor "CHST14" Topic sulfotransferases
4 results on '"CHST14"'

1. Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome.

Author

Kosho T, Mizumoto S, Watanabe T, Yoshizawa T, Miyake N, and Yamada S

Subjects
Chondroitin Sulfates metabolism, Dermatan Sulfate metabolism, Ehlers-Danlos Syndrome genetics, Ehlers-Danlos Syndrome metabolism, Female, Humans, Male, Pedigree, Phenotype, Antigens, Neoplasm genetics, DNA-Binding Proteins genetics, Ehlers-Danlos Syndrome pathology, Neoplasm Proteins genetics, Sulfotransferases genetics
Abstract

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.

Published
2019
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2. Structural alteration of glycosaminoglycan side chains and spatial disorganization of collagen networks in the skin of patients with mcEDS-CHST14.

Author

Hirose T, Takahashi N, Tangkawattana P, Minaguchi J, Mizumoto S, Yamada S, Miyake N, Hayashi S, Hatamochi A, Nakayama J, Yamaguchi T, Hashimoto A, Nomura Y, Takehana K, Kosho T, and Watanabe T

Subjects
Adolescent, Adult, Carbohydrate Sequence, Case-Control Studies, Child, Child, Preschool, Collagen chemistry, Collagen ultrastructure, Decorin metabolism, Dermatan Sulfate metabolism, Extracellular Matrix genetics, Extracellular Matrix metabolism, Female, Glycosaminoglycans chemistry, Glycosaminoglycans ultrastructure, Humans, Male, Molecular Conformation, Mutation, Protein Multimerization, Protein Structure, Quaternary, Skin pathology, Structure-Activity Relationship, Sulfotransferases metabolism, Young Adult, Collagen metabolism, Ehlers-Danlos Syndrome genetics, Ehlers-Danlos Syndrome metabolism, Ehlers-Danlos Syndrome pathology, Glycosaminoglycans metabolism, Skin metabolism, Skin ultrastructure, Sulfotransferases genetics
Abstract

Musculocontractural Ehlers-Danlos syndrome (mcEDS) due to CHST14/D4ST1 deficiency (mcEDS-CHST14) is a recently delineated type of EDS caused by biallelic loss-of-function mutations in CHST14, which results in the depletion of dermatan sulfate (DS). Clinical characteristics of mcEDS-CHST14 consist of multiple malformations and progressive fragility-related manifestations, including skin hyperextensibility and fragility. Skin fragility is suspected to result from the impaired assembly of collagen fibrils caused by alteration of the glycosaminoglycan (GAG) chain of decorin-proteoglycan (PG) from DS to chondroitin sulfate (CS). This systematic investigation of the skin pathology of patients with mcEDS-CHST14 comprised both immunostaining of decorin and transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains. Collagen fibrils were dispersed in the affected papillary to reticular dermis; in contrast, they were regularly and tightly assembled in controls. Moreover, the fibrils exhibited a perpendicular arrangement to the affected epidermis, whereas fibrils were parallel to control epidermis. Affected GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils; in contrast, those of controls were curved, maintaining close contact with attached collagen fibrils. This is the first observation of compositional alteration, from DS to CS, of GAG side chains, which caused structural alteration of GAG side chains and resulted in spatial disorganization of collagen networks; this presumably disrupted the ring-mesh structure of GAG side chains surrounding collagen fibrils. McEDS-CHST14 provides a critical example of the importance of DS in GAG side chains of decorin-PG during assembly of collagen fibrils in maintenance of connective tissues., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2019
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3. Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency

Author

Naomichi Matsumoto, Heng H Sin, Keng Wee Teik, Shuhei Yamada, Ai Unzaki, Shuji Mizumoto, Fransiska Malfait, Sara Markholt, Noriko Miyake, Charlotte Kvist Lautrup, Tomoki Kosho, Delfien Syx, and Irene K Nielsen

Subjects
Male, 0301 basic medicine, Connective Tissue Disorder, Pathology, medicine.medical_specialty, clinical features, Adolescent, lcsh:QH426-470, 030105 genetics & heredity, musculocontractural EDS-DSE, dermatan sulfate, Dermatan sulfate, musculocontractural EDS‐DSE, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, ADDUCTED THUMB, Loss of Function Mutation, Medicine and Health Sciences, Genetics, Humans, Medicine, Craniofacial, Hypertelorism, Molecular Biology, Genetics (clinical), delineation, business.industry, Chondroitin Sulfates, Original Articles, medicine.disease, Hypoplasia, Sclera, lcsh:Genetics, Phenotype, 030104 developmental biology, medicine.anatomical_structure, chemistry, Ehlers–Danlos syndrome, Original Article, Ehlers-Danlos Syndrome, Female, CHST14, Sulfotransferases, medicine.symptom, business, Palmar crease
Abstract

Background Musculocontractural Ehlers–Danlos Syndrome (mcEDS) is a rare connective tissue disorder caused by biallelic loss‐of‐function variants in CHST14 (mcEDS‐CHST14) or DSE (mcEDS‐DSE), both of which result in defective dermatan sulfate biosynthesis. Forty‐one patients with mcEDS‐CHST14 and three patients with mcEDS‐DSE have been described in the literature. Methods Clinical, molecular, and glycobiological findings in three additional patients with mcEDS‐DSE were investigated. Results Three patients from two families shared craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia), skeletal features (pectus and spinal deformities, characteristic finger shapes, progressive talipes deformities), skin features (fine or acrogeria‐like palmar creases), and ocular refractive errors. Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3. No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS. Conclusion McEDS‐DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS‐CHST14. However, the burden of symptoms seems lower in patients with mcEDS‐DSE., Clinical, molecular, and glycobiological findings in three additional patients from two families with musculocontractural Ehlers–Danlos syndrome (mcEDS‐DSE) are described. McEDS‐DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS‐CHST14. However, the burden of symptoms seems lower in patients with mcEDS‐DSE.

Published
2020
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4. Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers-Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis

Author

Ingrid Hausser, Jenny Morton, Merel C. Maiburg, Ingrid M.B.H. van de Laar, Delfien Syx, Tim Van Damme, Sofie Symoens, Anne De Paepe, Miguel del Campo, Trinh Hermanns-Lê, Fransiska Malfait, Mohnish Suri, and Clinical Genetics

Subjects
Male, Decorin, Biopsy, Iduronic acid, DSE, Case Reports, Review, EDS, chemistry.chemical_compound, Genetics(clinical), Non-U.S. Gov't, Child, Genetics (clinical), Skin, Medicine(all), Dermatan sulfate epimerase-1, Research Support, Non-U.S. Gov't, Exons, Extracellular Matrix, Neoplasm Proteins, Pedigree, DNA-Binding Proteins, medicine.anatomical_structure, Phenotype, Biochemistry, Female, Collagen, CHST14, Sulfotransferases, Adult, medicine.medical_specialty, Adolescent, Molecular Sequence Data, Connective tissue, Dermatan Sulfate, Biology, Research Support, Dermatan sulfate, Genetic Heterogeneity, Young Adult, Antigens, Neoplasm, Internal medicine, medicine, Genetics, Journal Article, Humans, Chondroitin sulfate, Amino Acid Sequence, RNA, Messenger, Genetic heterogeneity, Facies, medicine.disease, Dermatan 4-O-sulfotransferase-1, Fibronectins, carbohydrates (lipids), Endocrinology, chemistry, Proteoglycan, Ehlers–Danlos syndrome, Mutation, biology.protein, Ehlers-Danlos Syndrome, Ehlers-Danlos syndrome, Sequence Alignment
Abstract

Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.

Published
2015

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