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

Hirose, Takuya; Takahashi, Naoki; Tangkawattana, Prasarn; Minaguchi, Jun; Mizumoto, Shuji; Yamada, Shuhei; Miyake, Noriko; Hayashi, Shujiro; Hatamochi, Atsushi; Nakayama, Jun; Yamaguchi, Tomomi; Hashimoto, Ayana; Nomura, Yasuya; Takehana, Kazushige; Kosho, Tomoki; Watanabe, Takafumi

doi:10.1016/j.bbagen.2018.12.006

Cited by 28 publications

(49 citation statements)

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“…Light microscopy of skin specimens (hematoxylin and eosin staining) from patients with compound heterozygous p.(Pro281Leu)/(Cys289Ser) or p.(Pro281Leu)/(Tyr293Cys) substitutions showed that fine collagen fibers were predominantly present in the reticular to papillary dermis; marked reduction of normally thick collagen bundles were also observed ( Figure 4A) [6]. Immunohistochemistry staining of decorin core protein in skin specimens from patients with compound heterozygous p.(Pro281Leu)/(CYs289Ser) or p.(Pro281Leu)/(Tyr293Cys) substitutions showed that decorin core protein was present on collagen fibers that were thin and filamentous without clear boundaries; in contrast, skin specimens from healthy controls showed decorin core protein on collagen fibers that were thick bundles with clear boundaries [31] ( Figure 4B). Transmission electron microscopy of skin specimens from five patients with compound heterozygous p.(Pro281Leu)/(Cys289Ser), p.(Pro281Leu)/(Tyr293Cys), or p.(Phe209Ser)/(Pro281Leu) substitutions showed that collagen fibrils were dispersed in the papillary to reticular dermis, whereas skin specimens from healthy controls exhibited collagen fibrils that were regularly and tightly assembled ( Figure 4C) [6,31].…”

Section: Pathological Findingsmentioning

confidence: 97%

“…Immunohistochemistry staining of decorin core protein in skin specimens from patients with compound heterozygous p.(Pro281Leu)/(CYs289Ser) or p.(Pro281Leu)/(Tyr293Cys) substitutions showed that decorin core protein was present on collagen fibers that were thin and filamentous without clear boundaries; in contrast, skin specimens from healthy controls showed decorin core protein on collagen fibers that were thick bundles with clear boundaries [31] ( Figure 4B). Transmission electron microscopy of skin specimens from five patients with compound heterozygous p.(Pro281Leu)/(Cys289Ser), p.(Pro281Leu)/(Tyr293Cys), or p.(Phe209Ser)/(Pro281Leu) substitutions showed that collagen fibrils were dispersed in the papillary to reticular dermis, whereas skin specimens from healthy controls exhibited collagen fibrils that were regularly and tightly assembled ( Figure 4C) [6,31]. Transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains on affected skin samples showed that GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils, whereas skin samples from healthy controls exhibited curved GAG chains that maintained close contact with attached collagen fibrils ( Figure 4D) [31].…”

Section: Pathological 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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Section: Pathological Findingsmentioning

confidence: 97%

Section: Pathological Findingsmentioning

confidence: 99%

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

Kosho

Mizumoto

Watanabe

et al. 2019

Genes

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“…In fact, in cross‐sections of healthy skin specimens, the majority of GAG chains appeared to be curved and in close contact with the outer curved contour of the collagen fibrils by TEM. In contrast, GAG chains appear to be linear in cross‐sections of skin biopsies from CHST14 patients in which DS has been replaced by CS . This might explain poorer formation and greater dispersion of collagen fibres compared to healthy individuals in the skin of CHST14 patients .…”

Section: Intracellular and Extracellular Consequences Of The Defects mentioning

confidence: 99%

“…In contrast, GAG chains appear to be linear in cross‐sections of skin biopsies from CHST14 patients in which DS has been replaced by CS . This might explain poorer formation and greater dispersion of collagen fibres compared to healthy individuals in the skin of CHST14 patients . The specific defect affecting decorin glycation and its relevance in collagen fibril assembly might account for the skin phenotype common to these disorders.…”

Section: Intracellular and Extracellular Consequences Of The Defects mentioning

confidence: 99%

“…On the basis of altered PG metabolism observed in Pseudoxanthoma elasticum (PXE, MIM 264800), Hirose et al [148] XYLT1 and XYLT2 variants have been suggested to modulate the skin phenotype in PXE [60]. Biallelic pathogenic variants in FAM20B have recently been described in two sibs affected by a lethal form of neonatal short limb dysplasia [61].…”

Section: Disorders Linked To Proteins Involved In the Synthesis Of Thmentioning

confidence: 99%

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Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

et al. 2019

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Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides that constitute the carbohydrate moiety covalently attached to the protein core of proteoglycans, macromolecules present on the cell surface and in the extracellular matrix. Several genetic disorders of bone and connective tissue are caused by mutations in genes encoding for glycosyltransferases, sulfotransferases and transporters that are responsible for the synthesis of sulfated GAGs. Phenotypically, these disorders all reflect alterations in crucial biological functions of GAGs in the development, growth and homoeostasis of cartilage and bone. To date, up to 27 different skeletal phenotypes have been linked to mutations in 23 genes encoding for proteins involved in GAG biosynthesis. This review focuses on recent genetic, molecular and biochemical studies of bone and connective tissue disorders caused by GAG synthesis defects. These insights and future research in the field will provide a deeper understanding of the molecular pathogenesis of these disorders and will pave the way for developing common therapeutic strategies that might be targeted to a range of individual phenotypes.

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Clinical and pathophysiological delineation of musculocontractural Ehlers—Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS‐ DSE ): A detailed and comprehensive glycobiological and pathological investigation in a novel patient

et al. 2022

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Musculocontractural Ehlers-Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS-DSE) is a rare connective tissue disorder. This is the first report describing the detailed and comprehensive clinical and pathophysiological features of mcEDS-DSE. The patient, with a novel homozygous nonsense variant (NM_013352.4:c.2601C>A:p.(Tyr867*)), exhibited mild skin hyperextensibility without fragility and small joint hypermobility, but developed recurrent large subcutaneous hematomas. Dermatan sulfate (DS) moieties on chondroitin sulfate/DS proteoglycans were significantly decreased, but remained present, in skin fibroblasts. Electron microscopy examination of skin specimens, including cupromeronic blue-staining to visualize glycosaminoglycan (GAG) chains, revealed coexistence of normally assembled collagen fibrils with attached curved GAG chains and dispersed collagen fibrils with linear GAG chains from attached collagen fibrils across interfibrillar spaces to adjacent fibrils. Residual activity of DS-epi1, encoded by DSE, and/or compensation by DS-epi2, a minor homolog of DS-epi1, may contribute to the mild skin involvement through this "mosaic" pattern of collagen fibril assembly.

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

Cited by 28 publications

References 50 publications

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

Bone and connective tissue disorders caused by defects in glycosaminoglycan biosynthesis: a panoramic view

Clinical and pathophysiological delineation of musculocontractural Ehlers—Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS‐ DSE ): A detailed and comprehensive glycobiological and pathological investigation in a novel patient

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