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Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

1
Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
2
Center for Medical Genetics, Shinshu University Hospital, Matsumoto 390-8621, Japan
3
Research Center for Supports to Advanced Science, Matsumoto 390-8621, Japan
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Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Japan
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Laboratory of Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Japan
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Division of Animal Research, Research Center for Supports to Advanced Science, Shinshu University, Matsumoto 390-8621, Japan
7
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
*
Author to whom correspondence should be addressed.
Genes 2020, 11(1), 43; https://doi.org/10.3390/genes11010043
Received: 12 December 2019 / Revised: 22 December 2019 / Accepted: 23 December 2019 / Published: 29 December 2019
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. View Full-Text
Keywords: musculocontractural Ehlers–Danlos Syndome; carbohydrate sulfotransferase-14 (CHST14)/dermatan 4-O-sulfotransferase-1 (D4ST1); CHST14; dermatan sulfate epimerase (DSE); DSE; dermatan sulfate (DS); decorin; collagen musculocontractural Ehlers–Danlos Syndome; carbohydrate sulfotransferase-14 (CHST14)/dermatan 4-O-sulfotransferase-1 (D4ST1); CHST14; dermatan sulfate epimerase (DSE); DSE; dermatan sulfate (DS); decorin; collagen
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Kosho, T.; Mizumoto, S.; Watanabe, T.; Yoshizawa, T.; Miyake, N.; Yamada, S. Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome. Genes 2020, 11, 43.

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