Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome
| Autor: | Noriko Miyake, Shuhei Yamada, Shuji Mizumoto, Tomoki Kosho, Takahiro Yoshizawa, Takafumi Watanabe |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
collagen 0301 basic medicine Pathology medicine.medical_specialty lcsh:QH426-470 Decorin carbohydrate sulfotransferase-14 (CHST14)/dermatan 4-O-sulfotransferase-1 (D4ST1) Dermatan Sulfate Connective tissue DSE Review 030105 genetics & heredity musculocontractural ehlers–danlos syndome Dermatan sulfate Glycosaminoglycan 03 medical and health sciences chemistry.chemical_compound Antigens Neoplasm Genetics medicine Humans Chondroitin sulfate Genetics (clinical) decorin chst14 Chondroitin Sulfates Carbohydrate sulfotransferase medicine.disease Neoplasm Proteins Pedigree carbohydrate sulfotransferase-14 (chst14)/dermatan 4-o-sulfotransferase-1 (d4st1) DNA-Binding Proteins lcsh:Genetics Phenotype dse 030104 developmental biology medicine.anatomical_structure chemistry Ehlers–Danlos syndrome Ehlers-Danlos Syndrome Female CHST14 Sulfotransferases dermatan sulfate (ds) Reticular Dermis dermatan sulfate epimerase (dse) |
| Zdroj: | Genes, Vol 11, Iss 1, p 43 (2019) Genes |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes11010043 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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