scholarly journals Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 43 ◽  
Author(s):  
Tomoki Kosho ◽  
Shuji Mizumoto ◽  
Takafumi Watanabe ◽  
Takahiro Yoshizawa ◽  
Noriko Miyake ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Dermatan Sulfate ◽  
Close Contact ◽  
Normal Skin ◽  
Collagen Fibrils ◽  
Ehlers Danlos Syndrome ◽  
Reticular Dermis ◽  
Pathogenic Variants ◽  
Recent Advances ◽  
Skin Stretching

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.

Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

2019 ◽  
Vol 56 (9) ◽  
pp. 629-638 ◽  
Author(s):  
Lisa Jean Ewans ◽  
Alison Colley ◽  
Carles Gaston-Massuet ◽  
Angelica Gualtieri ◽  
Mark J Cowley ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Clinical Features ◽  
Vascular Complications ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Mineral Density ◽  
Ehlers Danlos Syndrome ◽  
Microarray Expression Data ◽  
Pathogenic Variants ◽  
Microarray Expression

BackgroundPathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease.MethodsReported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features.ResultsKey clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder.ConclusionThese data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

Systematic investigation of the skin in Chst14−/− mice: A model for skin fragility in musculocontractural Ehlers–Danlos syndrome caused by CHST14 variants (mcEDS-CHST14)

Glycobiology ◽  
2020 ◽  
Author(s):  
Takuya Hirose ◽  
Shuji Mizumoto ◽  
Ayana Hashimoto ◽  
Yuki Takahashi ◽  
Takahiro Yoshizawa ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Anion Exchange ◽  
Dermatan Sulfate ◽  
Systematic Investigation ◽  
Exchange Chromatography ◽  
Collagen Fibrils ◽  
Loss Of Function ◽  
Ehlers Danlos Syndrome ◽  
Skin Fragility ◽  
Danlos Syndrome

Abstract Loss-of-function variants in CHST14 cause a dermatan 4-O-sulfotransferase deficiency named musculocontractural Ehlers–Danlos syndrome-CHST14 (mcEDS-CHST14), resulting in complete depletion of the dermatan sulfate moiety of decorin glycosaminoglycan (GAG) chains, which is replaced by chondroitin sulfate. Recently, we uncovered structural alteration of GAG chains in the skin of patients with mcEDS-CHST14. Here, we conducted the first systematic investigation of Chst14 gene-deleted homozygote (Chst14−/−) mice. We used skin samples of wild-type (Chst14+/+) and Chst14−/− mice. Mechanical fragility of the skin was measured with a tensile test. Pathology was observed using light microscopy, decorin immunohistochemistry and electron microscopy (EM) including cupromeronic blue (CB) staining. Quantification of chondroitin sulfate and dermatan sulfate was performed using enzymatic digestion followed by anion-exchange HPLC. In Chst14−/− mice, skin tensile strength was significantly decreased compared with that in Chst14+/+ mice. EM showed that collagen fibrils were oriented in various directions to form disorganized collagen fibers in the reticular layer. Through EM-based CB staining, rod-shaped linear GAG chains were found to be attached at one end to collagen fibrils and protruded outside of the fibrils, in contrast to them being round and wrapping the collagen fibrils in Chst14+/+ mice. A very low level of dermatan sulfate disaccharides was detected in the skin of Chst14−/− mice by anion-exchange chromatography. Chst14−/− mice, exhibiting similar abnormalities in the GAG structure of decorin and collagen networks in the skin, could be a reasonable model for skin fragility of patients with mcEDS-CHST14, shedding light on the role of dermatan sulfate in maintaining skin strength.

scholarly journals Myopathy Associated With Dermatan Sulfate-Deficient Decorin and Myostatin in Musculocontractural Ehlers-Danlos Syndrome: A Mouse Model Investigation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuko Nitahara-Kasahara ◽  
Guillermo Posadas-Herrera ◽  
Shuji Mizumoto ◽  
Aki Nakamura-Takahashi ◽  
Yukiko U. Inoue ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dermatan Sulfate ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Ehlers Danlos Syndrome ◽  
Pathogenic Variants ◽  
Myogenic Activity ◽  
Small Muscle ◽  
Danlos Syndrome ◽  
Deficient Mice

Carbohydrate sulfotransferase 14 (CHST14) encodes dermatan 4-O-sulfotransferase 1, a critical enzyme for dermatan sulfate (DS) biosynthesis. Musculocontractural Ehlers-Danlos syndrome (mcEDS) is associated with biallelic pathogenic variants of CHST14 and is characterized by malformations and manifestations related to progressive connective tissue fragility. We identified myopathy phenotypes in Chst14-deficient mice using an mcEDS model. Decorin is a proteoglycan harboring a single glycosaminoglycan chain containing mainly DS, which are replaced with chondroitin sulfate (CS) in mcEDS patients with CHST14 deficiency. We studied the function of decorin in the skeletal muscle of Chst14-deficient mice because decorin is important for collagen-fibril assembly and has a myokine role in promoting muscle growth. Although decorin was present in the muscle perimysium of wild-type (Chst14+/+) mice, decorin was distributed in the muscle perimysium as well as in the endomysium of Chst14–/– mice. Chst14–/– mice had small muscle fibers within the spread interstitium; however, histopathological findings indicated milder myopathy in Chst14–/– mice. Myostatin, a negative regulator of protein synthesis in the muscle, was upregulated in Chst14–/– mice. In the muscle of Chst14–/– mice, decorin was downregulated compared to that in Chst14+/+ mice. Chst14–/– mice showed altered cytokine/chemokine balance and increased fibrosis, suggesting low myogenic activity in DS-deficient muscle. Therefore, DS deficiency in mcEDS causes pathological localization and functional abnormalities of decorin, which causes disturbances in skeletal muscle myogenesis.

scholarly journals Muscle pathophysiology in mouse models of musculocontractural Ehlers-Danlos syndrome due to CHST14 mutations (mcEDS-CHST14), generated through CRISPR/Cas9-mediated genomic editing

2021 ◽  
Author(s):  
Yuko Nitahara-Kasahara ◽  
Shuji Mizumoto ◽  
Yukiko U. Inoue ◽  
Shota Saka ◽  
Guillermo Posadas-Herrera ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Models ◽  
Genome Engineering ◽  
Dermatan Sulfate ◽  
Treatment Strategies ◽  
Mutant Mice ◽  
Wild Type ◽  
Ehlers Danlos Syndrome ◽  
Pathogenic Variants ◽  
Danlos Syndrome

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is caused by generalized depletion of dermatan sulfate (DS) due to biallelic pathogenic variants in CHST14 encoding dermatan 4-O-sulfotransferase 1 (D4ST1) (mcEDS-CHST14). Here, we generated mouse models for mcEDS-CHST14 carrying homozygous mutations (1 bp deletion or 6 bp insertion/10 bp deletion) in Chst14 through CRISPR/Cas9-genome engineering to overcome perinatal lethality in conventional Chst14-deleted knockout mice. DS depletion was detected in the skeletal muscle of these genome-edited mutant mice, consistent with loss of D4ST1 activity. The mutant mice showed common pathophysiological features, regardless of the variant, including growth impairment and skin fragility. Notably, we identified myopathy-related phenotypes. Muscle histopathology showed variation in fiber size and spread of the muscle interstitium. Decorin localized diffusely in the spread endomysium and perimysium of skeletal muscle, unlike in wild-type mice. The mutant mice showed lower grip strength and decreased exercise capacity compared to wild-type, and morphometric evaluation demonstrated thoracic kyphosis in mutant mice. The established CRISPR/Cas9-engineered Chst14 mutant mice would be a useful model to further our understanding of the mcEDS pathophysiology and in the development of novel treatment strategies.

Ultrastructure of Liver in Lactosyl Ceramidosis

1971 ◽  
Vol 29 ◽  
pp. 312-313
Author(s):  
Z. Hruban ◽  
J. R. Esterly ◽  
G. Dawson ◽  
A. O. Stein
Keyword(s):  
Connective Tissue ◽  
Liver Biopsy ◽  
Osmium Tetroxide ◽  
Close Contact ◽  
Multivesicular Bodies ◽  
Bile Canaliculi ◽  
Dense Bodies ◽  
Marginal Plates ◽  
Membranous Material ◽  
Perichromatin Granules

Samples of a surgical liver biopsy from a patient with lactosyl ceramidosis were fixed in paraformaldehyde and postfixed in osmium tetroxide. Hepatocytes (Figs. 1, 2) contained 0.4 to 2.1 μ inclusions (LCI) limited by a single membrane containing lucid matrix and short segments of curved, lamellated and circular membranous material (Fig. 3). Numerous LCI in large connective tissue cells were up to 11 μ in diameter (Fig. 2). Heterogeneous dense bodies (“lysosomes”) were few and irregularly distributed. Rough cisternae were dilated and contained smooth vesicles and surface invaginations. Close contact with mitochondria was rare. Stacks were small and rare. Vesicular rough reticulum and glycogen rosettes were abundant. Smooth vesicular reticulum was moderately abundant. Mitochondria were round with few cristae and rare matrical granules. Golgi complex was seen rarely (Fig. 1). Microbodies with marginal plates were usual. Multivesicular bodies were very rare. Neutral lipid was rare. Nucleoli were small and perichromatin granules were large. Small bile canaliculi had few microvilli (Fig. 1).

Banded Structures in the Connective Tissue of Meningioma

1976 ◽  
Vol 34 ◽  
pp. 234-235
Author(s):  
C. N. Sun ◽  
H. J. White
Keyword(s):  
Connective Tissue ◽  
Osmium Tetroxide ◽  
Uranyl Acetate ◽  
Collagen Fibrils ◽  
Lead Citrate ◽  
Connective Tissues ◽  
Native Collagen ◽  
Routine Procedures

Previously, we have reported on extracellular cross-striated banded structures in human connective tissues of a variety of organs (1). Since then, more material has been examined and other techniques applied. Recently, we studied a fibrocytic meningioma of the falx. After the specimen was fixed in 4% buffered glutaraldehyde and post-fixed in 1% buffered osmium tetroxide, other routine procedures were followed for embedding in Epon 812. Sections were stained with uranyl acetate and lead citrate. There were numerous cross striated banded structures in aggregated bundle forms found in the connecfive tissue of the tumor. The banded material has a periodicity of about 450 Å and where it assumes a filamentous arrangement, appears to be about 800 Å in diameter. In comparison with the vicinal native collagen fibrils, the banded material Is sometimes about twice the diameter of native collagen.

Platelet Adhesion to Native Collagens Involves Proteoglycans and May Be a Two-Step Process

1987 ◽  
Vol 58 (02) ◽  
pp. 786-789 ◽  
Author(s):  
O Behnke
Keyword(s):  
Electron Microscope ◽  
Platelet Adhesion ◽  
Close Contact ◽  
Blood Platelets ◽  
Collagen Fibrils ◽  
Platelet Membrane ◽  
Step Process ◽  
Rat Blood ◽  
Wide Gap ◽  
Rat Tail

SummaryAdhesion of rat blood platelets to native rat tail collagen fibrils was studied in the electron microscope under conditions that preserved collagen-associated proteoglycans (CAPG). The CAPG molecules were aligned in chain-like configurations that encircled the fibrils with a 65 nm period; they appeared to coat the fibrils completely and extended 60-100 nm away from the fibril. The initial platelet-fibril contact occurred between the platelet glycocalyx and the CAPG of the fibrils i.e. between two surfaces with net-negative charges. When close contact was established between the fibril surface proper and the platelet membrane, CAPG were not identified in the area of contact, and the collagen-platelet distance was reduced to a ~10-12 nm wide gap traversed by delicate links in register with fibril periodicities.

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