Dataset Information

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome.

ABSTRACT: Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.

SUBMITTER: Mizumoto S

PROVIDER: S-EPMC9957132 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Histories of Dermatan Sulfate Epimerase and Dermatan 4-<i>O</i>-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome.

Mizumoto Shuji S Yamada Shuhei S

Genes 20230216 2

Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-<i>O</i>-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause th ...[more]

PMID: 36833436

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Project description:Of all live births with congenital anomalies, approximately one-third exhibit deformities of the head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE). Studies in mice have extended our understanding of DS-epi1 in connective tissue maintenance; however, its role in fetal development is not understood. We demonstrate that DS-epi1 is important for the generation of isolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos. The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures. Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin. Thus, our work indicates a functional link between DS and NC cell migration. We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS, which might facilitate the diagnosis and development of therapies for this distressing condition. Moreover, the presented correlations between human DS-epi1 expression and gene sets of mesenchymal character, invasion and metastasis in neuroblastoma and malignant melanoma suggest an association between DS and NC-derived cancers.

Dataset Information

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome.

Publications

Histories of Dermatan Sulfate Epimerase and Dermatan 4-<i>O</i>-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome.

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