Next Article in Journal
A Novel Homozygous Nonsense Variant in the DYM Underlies Dyggve-Melchior-Clausen Syndrome in Large Consanguineous Family
Next Article in Special Issue
Detailed Courses and Pathological Findings of Colonic Perforation without Diverticula in Sisters with Musculocontractural Ehlers–Danlos Syndrome Caused by Pathogenic Variant in CHST14 (mcEDS-CHST14)
Previous Article in Journal
The rs3825807 Polymorphism of ADAMTS7 as a Potential Genetic Marker for Myocardial Infarction in Slovenian Subjects with Type 2 Diabetes Mellitus
Previous Article in Special Issue
Mouse Models of Musculocontractural Ehlers-Danlos Syndrome
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Genes
Volume 14
Issue 2
10.3390/genes14020509
genes-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

by
Shuji Mizumoto
* and
Shuhei Yamada
Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
*
Author to whom correspondence should be addressed.
Genes 2023, 14(2), 509; https://doi.org/10.3390/genes14020509
Submission received: 11 January 2023 / Revised: 11 February 2023 / Accepted: 13 February 2023 / Published: 16 February 2023
(This article belongs to the Special Issue Musculocontractural Ehlers-Danlos Syndrome and the Biological Role of Dermatan Sulfate)
Browse Figures
Review Reports Versions Notes

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.

Graphical Abstract

1. Introduction

Dermatan sulfate (DS) is classified as a sulfated glycosaminoglycan (GAG) that is a linear polysaccharide chain, and it is covalently attached to the core proteins of proteoglycans (PGs) [1,2,3,4,5]. DS was first isolated from porcine skin by Karl Meyer in the 1940s [6]. DS-PGs have been purified from bovine tendon [7], bovine sclera [8], porcine skin [9], calf skin [10], and bovine periodontal ligament [11]. Two distinct populations of DS-PGs have been found in bovine sclera and cartilage [8,12]. A complete amino acid sequence of a DS-PG, decorin, has been deduced for human [13], bovine [14], chick [15], and rat [16] forms (Table 1). A complete amino acid sequence of another DS-PG, biglycan, has been identified for human [17] and bovine [18] forms. A DS-PG, PG-Lb/epiphycan, has been identified from chick embryonic epiphyseal cartilage [19]. Furthermore, a soluble DS-PG, endocan, has been isolated as an endothelial cell-specific molecule [20,21].
The DS side chain of DS-PGs is composed of an alternating disaccharide unit, N-acetyl-D-galactosamineβ1–4L-iduronic acid (-3GalNAcβ1–4IdoUAα1-)n, with 50–200 repeats that are modified by sulfation (Figure 1). The repeating disaccharide region of DS is covalently bound to the serine (Ser) residue of a specific core protein through the common GAG-linker region tetrasaccharide, glucuronic acidβ1-3galactoseβ1-3galactoseβ1-4xyloseβ1-O-Ser (GlcUA-Gal-Gal-Xyl-O-Ser) [22,23,24,25,26,27] (Figure 1). DS-PGs encompassing DS side chains control a wide range of biological functions including the signal transduction via binding to effector proteins, anti-coagulation, wound healing, and assembly of extracellular matrices [2,3,4,5,28,29,30,31,32,33,34,35]. Thus, DS side chains on PGs are essential for normal development as well as the maintenance of fundamental biological functions. This review focuses on histories of the DS-biosynthetic enzymes dermatan sulfate-epimerase (DSE) and dermatan 4-O-sulfotransferase (D4ST).

2. Biosynthesis of DS Side Chains on PGs

2.1. GAG-Protein Linker Region

Initial biosynthesis of DS side chains is evoked by the construction of a common GAG-protein linker region tetrasaccharide, GlcUA-Gal-Gal-Xy-O-Ser (Figure 2) [1,22,23,24,25,26,27]. XYLT1 and XYLT2 encode β-xylosyltransferases (XylT), which transfer a Xyl moiety from uridine diphosphate (UDP)-Xyl to specific serine residues in the core proteins of PGs biosynthesized in the endoplasmic reticulum and/or cis-Golgi compartments [36,37,38,39,40,41,42,43,44]. B4GALT7 encodes β1,4-galactosyltransferase-I (GalT-I), which transfers a β4Gal moiety from UDP-Gal to Xyl-O-Ser in the core proteins of PGs in the Golgi apparatus [37,45,46,47,48,49]. GalT-I interacts with XylT, which has been demonstrated through co-immunoprecipitation and the course purification of GalT-I [50,51]. B3GALT6 encodes β1,3-galactosyltransferase-II (GalT-II), which transfers a β3Gal moiety from UDP-Gal to Galβ1-4Xylβ1-O-Ser in the core proteins of PGs [45,46,52]. B3GAT3 encodes β1,3-glucuronosyltransferase-I (GlcAT-I), which transfers a β3GlcUA moiety from UDP-GlcUA to Galβ1-3Galβ1-4Xylβ1-O-Ser in the core proteins of PGs (Figure 2) [53,54,55,56,57].

2.2. Repeating Disaccharide Region of DS

After the formation of the linker region tetrasaccharide, GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser, the first GalNAc residue is transferred to the tetrasaccharide-Ser on specific core proteins of PGs by β1,4-N-acetylgalactosaminyltransferase-I (GalNAcT-I) (Figure 2) [58,59,60]. CSGALNACT1 and CSGALNACT2 genes encoding GalNAcT-I have been identified [61,62,63,64]. CSGALNACT1 and CSGALNACT2 show GalNAcT-II activity (see below) in addition to GalNAcT-I activity [61,62,63,64].
After the attachment of the first β4GalNAc by GalNAcT-I, the resultant nascent pentasaccharide, GalNAcβ1-4GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser, is elongated further by alternate additions of β3GlcUA and β4GalNAc from UDP-GlcUA and UDP-GalNAc, which are catalyzed by CS-β1,3glucuronyltransferase-II (CS-GlcAT-II) and β1,4N-acetylgalactosaminyltransferase-II (GalNAcT-II), respectively (Figure 2) [65,66,67,68,69,70,71,72]. Chondroitin synthase (ChSy), a single polypeptide chain, has dual enzymatic activities, CS-GlcAT-II and GalNAcT-II [73], whereas chondroitin polymerizing factor (ChPF) showed only weak GalNAcT-II activity [74]. In spite of the dual enzymatic activities of ChSy, ChSy itself cannot achieve polymerization reactions to build up the repeating disaccharide units of chondroitin in vitro. However, the association of ChSy with ChPF, resulting in the enzyme complex, polymerizes a repeating disaccharide region of chondroitin, [-4GlcUAβ1-3GalNAcβ1-]n [74]. To date, four genes, CHSY1, CHSY3, CHPF, and CHPF2, have been characterized as CS polymerases (Figure 2) [73,74,75,76,77,78,79].
Following and/or during the formation of the chondroitin precursor chain by ChSy/ChPF family members, the GlcUA moieties are subsequently converted into IdoUA by chondroitin GlcUA-C5-epimerase/dermatan sulfate epimerase (DSE), which epimerizes the C-5 carboxy group of GlcUA residues (Figure 1 and Figure 2) (Table 2) [80,81,82,83,84,85,86,87]. Two genes, DSE and DSEL, encoding DSE have been identified, and their gene products have demonstrated GlcUA-C5-epimerase activity [88,89,90]. It should be noted that DSE is identical to SART2 (squamous cell carcinoma antigen recognized by T cells 2), which encodes a protein with unknown function highly expressed in cancer cells and tissues [91], and that DSEL is identical to C18orf4, which is a candidate gene for a bipolar disorder [92].
After and/or during construction of the repeating disaccharide region of dermatan, [-4IdoUAα1-3GalNAcβ1-]n, there is further modification with sulfation at the C-2 and C-4 positions of IdoUA and GalNAc residues in dermatan by uronosyl 2-O-sulfotransferase (UST) and dermatan 4-O-sulfotransferase (D4ST), respectively, using the sulfate donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) (Table 2) [93,94,95,96,97,98]. CHST14 and UST have been identified as the genes encoding D4ST and UST, respectively [94,95,97]. 4-O-Sulfation, but not 2-O-sulfation, is predominant in mammals.

3. Roles of DSE and D4ST in Biosynthesis of DS

3.1. DSE

DSE (also known as chondroitin-glucuronate C5-epimerase) converts GlcUA into IdoUA by epimerization of the C-5 carboxy group of GlcUA moieties in the repeating disaccharide region of the chondroitin precursor chain, [-4GlcUAβ1-3GalNAcβ1-]n, to construct the disaccharide region of dermatan, [-4IdoUAα1-3GalNAcβ1-]n (Figure 2). In the 1970s, Malmström et al. demonstrated that the formation of IdoUA from the GlcUA residue occurred at the polymer level together with sulfation using fibroblast extract [80], which suggests the requirement of sulfation for the epimerization of GlcUA. Furthermore, Malmström revealed an important feature of the epimerization of GlcUA into IdoUA: the release of H from C-5 of the target GlcUA [81]. The incorporation of 3H into the GlcUA residue of chondroitin from 3H2O, or the liberated 3H, which was released from chondroitin with 5-3H-labeled GlcUA residues, can be quantified by liquid scintillation counting [82,83,84]. Dermatan is a better substrate than chondroitin for DSE, from human embryonic fibroblasts, but not CS or DS [83,86]. Tiedemann and Malmström et al. demonstrated high and low levels of chondroitin-glucuronate C5-epimerase activity in human lung fibroblasts and bovine chondrocyte cultures from nasal cartilage, respectively, whereas high 4-O-sulfotransferase activity was detected in both cells [87]. These findings suggest that 4-O-sulfation on GalNAc residues in both DS and CS may block DSE to fix the configuration of GlcUA and IdoUA.
In 2006, Maccarana et al. identified the gene SART2, encoding chondroitin-glucuronate C5-epimerase [88]. The enzyme was purified from the bovine spleen, in which GlcUA C5-epimerase activity is the highest among various tissues examined. Partially purified proteins were subjected to mass spectrometry analysis after treatment with trypsin. SART2, an unknown protein expressed in cancer cells and tissues [91], was identified from the 89-kDa band. There is no orthologous gene in the nematode (Caenorhabditis elegans) or fruit fly (Drosophila melanogaster). This is consistent with the finding that there is no DS in these organisms [99,100,101]. The recombinant SART2 protein exhibited strong GlcUA C5-epimerase activity. They proposed renaming SART2 as chondroitin-glucuronate C5-epimerase or DS-epimerase [88]. Currently, DSE is widely utilized as the name of the enzyme and gene. Research by Maccarana and Malmström involving the long-term study of DSE has greatly contributed to the elucidation of the functions of DSE as well as DS, and understanding of the pathogenic mechanisms of Ehlers-Danlos syndrome (EDS) with mutations in DSE, as described below.
In 2009, Maccarana et al. generated Dse-deficient mice [102], which exhibited reductions in DSE activity as well as DS, a smaller body size, a kinked tail at birth, and thicker collagen fibrils in the dermis and hypodermis [102]. Furthermore, defects in the fetal abdominal wall, exencephaly, spina bifida, and the impaired migration of aortic smooth muscle cells were also detected in Dse–/– mice [103,104]. Dse-deficient mice also showed a reduction in the migration of skin-derived dendritic cells from the skin to draining lymph nodes that is a prerequisite for encounter with antigens [105]. Consequently, the initiation of the cellular and humoral immune response was diminished in Dse−/− mice.
In 2016, Gouignard et al. generated Xenopus laevis with knockdown of Dse and Dsel using morpholino antisense oligonucleotides [106]. Although the knockdown of Dse did not affect the formation of early neural crest progenitors, the epimerase activity and extent of neural crest cell migration were decreased in the morphants of Dse, which led to a decrease in neural crest-derived craniofacial skeleton, melanocytes, and dorsal fin structures. On the other hand, the knockdown of Dsel did not show clear phenotype except for a 12% decrease in DSE activity [106].
DS and/or DS-PGs are elevated in malignant cells and in the stroma [107], which is in agreement with an increase in DSE [108]. Thelin et al. demonstrated that a human esophageal squamous cell carcinoma treated with DSE-shRNA exhibited reduced migration and invasion abilities in vitro. Furthermore, these cells exhibited reduced cellular interaction with hepatocyte growth factor, inhibition of pERK1/2 signaling, and diminished focal adhesion formation and actin cytoskeleton dynamics [108]. These findings suggest that DS may contribute to the proliferation, invasion, and metastasis of esophageal squamous cell carcinoma via its binding with effector proteins such as hepatocyte growth factor and fibroblast growth factor at the cell surface and/or extracellular matrix.
In 2013, Müller et al. reported that EDS musculocontractural type 2 was caused by the homozygous mutation p.Ser268Leu in DSE (Table 2 and Table 3) [109]. The clinical manifestations of their patient presented hypermobility of the finger, elbow, and knee joints, atrophic scars on skin, contracture of the thumbs and feet, and characteristic facial features [109]. DSE activities of recombinant p.Ser268Leu-DSE enzyme, as well as skin fibroblast cultures from the patient, were markedly weaker than in a respective control [109]. It should be noted that Mizumoto et al. developed a methodology to measure DSE activity without using a radioisotope such as 5-3H-labeled GlcUA in chondroitin and 3H2O. Namely, it utilized a CS-specific degrading enzyme, chondroitinase AC, fluorescent labelling, and an anion-exchange HPLC, based on the previous finding that dermatan is a better substrate than chondroitin for DSE [83], and that chondroitinase AC can act on a non-sulfated disaccharide unit, -GlcUA-GalNAc-, but that chondroitinase B, a DS-specific degrading enzyme, cannot act on a non-sulfated disaccharide unit, -IdoUA-GalNAc-. The reaction mixture containing the enzyme source, buffer, and desulfated DS (dermatan), was incubated at 37 °C. The chondroitin moiety of the reaction products with partial conversion from the IdoUA residue into the GlcUA residue can be digested with chondroitinase AC. The resultant di- or oligo-saccharides were labeled with a fluorophore at the reducing end, which was subjected to anion-exchange HPLC. When we analyzed the DSE activity and level of DS in the patient fibroblasts, significant decreases in the amount of DS disaccharide were detected in fibroblasts from the patient, accompanied by a decrease in the DSE activity, compared with those in fibroblasts from a healthy subject [109]. To date, nine cases have been reported as EDS musculocontractural type 2 caused by the mutation, p.Gly216Glufs*3, p.Arg267Gly, p.Ser268Leu, p.Tyr320*, p.Val333Cysfs*4, pPro384Trpfs*9, and pHis588Arg, in DSE [109,110,111,112,113].

3.2. DSEL/DSE2

In 2009, Pacheco et al. demonstrated that the second DSE, DSE2, encoded by DSEL, was identified as a homolog of DSE [90]. DSE2 consists of 1222 amino acids, which is larger than DSE (958 aa), has an epimerase domain, ~700 amino acids, at the N-terminus, and a predicted O-sulfotransferase domain at the C-terminus [90]. DSE2/DSEL has epimerase activity, but no sulfotransferase activity toward desulfated DS, dermatan, and partially desulfated CS-A and CS-C [90]. The sulfotransferase domain in DSE2 has never been elucidated. It has been proposed as two epimerases, DS-epi1 and DS-epi2, encoded by DSE and DSEL genes, respectively [90]. To clarify the capacity of DSE and DSE2 in the formation of IdoUA in the DS chain, both genes were overexpressed in human embryonic kidney 293 cells. Overexpression of DSE led to the formation of IdoUA-block in both decorin and biglycan side chains, whereas overexpression of DSE2 resulted in the formation of IdoUA/GlcUA-hybrid structures, but not IdoUA-block [90]. Thus, tissues or cells such as the brain, in which DSEL is highly expressed more than DSE [114], may produce the CS/DS hybrid chain rather than a genuine DS chain. In fact, CS and DS chains in the mouse brain are predominantly present as hybrid structures containing both GlcUA and IdoUA residues in a single GAG chain [114,115,116].
In 2021, Bartolini et al. generated Dsel-deficient mice [117]. Although the Dsel–/– mice showed reduced epimerase activity in the brain (89%), kidney (55%), spleen (44%), liver (38%), lung (34%), and skin (24% reduction) compared to that in wild-type tissues, Dsel–/– mice exhibited no morphological, histological, or anatomical defects. The level of the IdoUA moiety in CS/DS from the newborn kidney and brain was reduced to 62 and 87% of wild-type mice, respectively, which may be consistent with the finding that DSEL was more predominantly expressed in the brain than DSE [91,92,117]. DSE may compensate for the loss of functions in DSEL.
In 2015, Stachtea et al. generated double knockout mice of Dse and Dsel [118]. They showed complete loss of DS, perinatal lethality, exencephaly, an umbilical hernia, and a kinked tail, suggesting that DS is essential for embryonic development.
In 2003, Goossens et al. reported that various homozygous or heterozygous mutations in DSEL, such as p.Val287Ile, p.Pro673Ser, p.Tyr730Cys, p.Pro942Ser, p.Ile1113Met, and a substitution of adenine to guanine in the 5′-non-coding region 546 bp upstream of the coding region, caused bipolar disorder [92]. In 2011, Shi et al. reported that a single nucleotide polymorphism, 75 kbp upstream of DSEL, caused a recurrent early-onset major depressive disorder [119]. Because DSEL, but not DSE, is predominantly expressed in the brain [91,92,117], the variants of DSEL may affect its neuronal functions.
In 2010, Zayed et al. reported that a congenital diaphragmatic hernia was caused by mutations in DSEL [120]. The probands showing diaphragmatic hernia have substitutions of amino acids: p.Met14Ile, p.Asn276Ser, p.Pro683Ser, p.Tyr740Cys, p.Thr842Ser, and p.Asp991Asn. Mouse Dsel was expressed in the murine diaphragm muscle on embryonic day (E) 13.5 by in situ hybridization using murine embryo sections [120]. Further analyses may be necessary to understand the pathogenic mechanisms leading to diaphragmatic hernia involving DS as well as DSEL.

3.3. CHST14/D4ST1

D4ST catalyzes the transfer of a sulfate group from an active sulfate, PAPS, to the C-4 hydroxy group of GalNAc residues in the repeating disaccharide region of dermatan, [IdoUA-GalNAc]n (Figure 2). In 2001, Tiedemann et al. demonstrated that D4ST activity in human lung fibroblast and bovine articular chondrocyte cultures was higher than that in bovine nasal chondrocyte cultures [87]. Furthermore, Eklund et al. demonstrated that D4ST activity was detected in cell lysate from cultured human embryonic fibroblasts [93]. It has been demonstrated that even though the DSE reaction is freely reversible during the conversion of uronic acids on chondroitin as well as dermatan, neither CS nor DS is recognized by DSE [83]. They proposed that the formation of IdoUA during biosynthesis of DS might be enhanced by 4-O-sulfation of the GalNAc residue, thereby being locked in the configuration of IdoUA [87].

3.3.1. Identification of CHST14/D4ST1 Gene

In 2000, Yamauchi et al. identified the gene, carbohydrate sulfotransferase 11 (CHST11), encoding chondroitin 4-O-sulfotransferase-1 (C4ST-1), which catalyzes the transfer of a sulfate group from PAPS to the C-4 hydroxy group of GalNAc residues in the repeating disaccharide region of chondroitin, [GlcUA-GalNAc]n (Figure 2), based on the protein sequence of purified C4ST from culture medium of rat chondrosarcoma after treatment with trypsin [121]. Subsequently, Hiraoka and Kang et al. identified CHST12 and CHST13, encoding C4ST-2 and C4ST-3, respectively [122,123]. In 2000 and 2001, Baenziger and colleagues identified two genes, CHST8 and CHST9, encoding GalNAc4ST-1 and GalNAc4ST-2, respectively, which transfer a sulfate group from PAPS to a terminal β1,4-linked GalNAc residue in GalNAcβ1-4GlcNAc- on N-linked oligosaccharides present on the glycoprotein hormones thyrotropin and lutropin [124,125].
In 2001, Evers et al. identified the gene CHST14, encoding D4ST-1, through a homology search using the amino acid sequence of the 4-O-sulfotransferase family [94]. Mikami et al. demonstrated the substrate specificities of D4ST-1, C4ST-1, and C4ST-2 [95]. Briefly, D4ST-1 generates IdoUA-GalNAc(4-O-sulfate)-rich clusters, a typical structure in mature DS chains. C4ST-2 transfers a sulfate to both GalNAc residues in -IdoUA-GalNAc-IdoUA- and -GlcUA-GalNAc-GlcUA- [95]. In 2009, Pacheco et al. demonstrated that the knockdown of D4ST-1 in human lung fibroblasts led to a marked reduction in IdoUA-containing structures in the DS chain [96]. Furthermore, in 2018, Tykesson et al. demonstrated that DSE, but not DSEL, forms a heterocomplex with D4ST-1, which is essential to form longer IdoA-containing chains [126]. Therefore, the cooperation of D4ST-1 and DSE by heterocomplex formation is necessary for the synthesis of repeating disaccharides, [-IdoUA-GalNAc(4-O-sulfate)-]n, in mature DS.

3.3.2. Knockout Mice of Chst14/D4st1

In 2011, Bian et al. generated D4st1/Chst14-deficient mice [127]. Neurospheres from Chst14–/– mice showed larger diameters and fewer total numbers than those from wild-type mice, caused by dysfunctions in the self-renewal and proliferation of neural stem cells [127]. The epitopes of monoclonal antibody 473HD that recognize the specific sulfation patterns -GlcUA-GalNAc(4-O-sulfate)-, -GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate)-, and -IdoUA-GalNAc(4-O-sulfate)- in CS-DS hybrid structures exist on radial glia and neurospheres [128,129]. Furthermore, a decrease in the number of neurospheres formed was observed after chondroitinase ABC or 473HD treatment [130]. In neurospheres generated from Chst14–/– mice, distribution of the 473HD epitope was decreased to 58% of that in wild-type neurospheres [127]. These findings indicate that D4ST-1 and DS are important for the self-renewal and differentiation of neural stem cells.
In 2013, Akyüz et al. demonstrated that Chst14–/– mice showed a higher proliferation rate and longer cell processes of cultured Schwann cells from nerves and dorsal roots, compared with those of wild-type mice [131]. Although the Chst14–/– mice were fertile, one third of the knockout mice died between E16.5 and E18.5 and/or within a few days after birth [131]. The weights of the kidney, liver, heart, tibia, and whole body, but not brain, were reduced in the Chst14–/– mice compared with wild-type littermates. These findings suggest that D4ST-1 and/or DS may be essential for early tissue development.
In 2018, Yoshizawa et al. demonstrated a significantly decreased amount of DS, an abnormal structure of the basement membrane of capillaries, an alteration in the vascular structure with ischemic and/or necrotic-like change, and a reduced weight of the placenta in the placenta derived from Chst14–/– mice, compared with wild-types [132]. These findings indicate that D4ST-1 and DS may be indispensable for placental vascular development, and help to elucidate several cases of perinatal lethality caused by a mutation in CHST14 [133].
In 2021, Hirose et al. demonstrated that DS exhibited a round conformation with wrapped collagen fibrils in wild-type mice, whereas rod-shaped linear CS side chains of decorin observed at one end of collagen fibrils protruded outside the fibrils in Chst14–/– mice [134]. Furthermore, the skin tensile strength of Chst14–/– mice was lower than that of wild-type mice. These findings indicate that the DS side chain of decorin plays roles in the architecture of collagen fibrils and supporting skin strength.
In 2021, Nitahara-Kasahara et al. demonstrated that elephant teeth, thoracic kyphosis, increased skin fragility, and a kinked tail were observed in Chst14–/– mice [135,136]. Moreover, they also found a reduction in DS disaccharide in muscle and myopathy-related phenotypes including spread of the muscle interstitium and variation in fiber size, which may lead to decreased exercise capacity and lower grip strength in Chst14–/– mice. These findings suggest that D4ST-1 and/or DS is essential for the myogenesis of skeletal muscle.

3.3.3. Human Genetic Disorders Caused by Mutations in CHST14/D4ST1

In 2009, Dünder et al. reported that adducted thumb–clubfoot syndrome in 11 probands from four families exhibited the homozygous mutations p.Val49*, p.Arg213Pro, and p.Tyr293Cys, and the complex heterozygous mutation p.Arg135Gly/p.Leu137Gln in CHST14 [133]. Adducted thumb–clubfoot syndrome is an autosomal recessive disorder characterized by congenital defects in the heart, kidneys, or intestines, connective tissue fragility with aging, thin and translucent skin, coagulopathy, facial clefting, a typical facial appearance, joint instability, and contracture of the thumbs and feet [137]. Five out of the eleven probands with adducted thumb–clubfoot syndrome died in early infancy or childhood. Furthermore, their studies showed a reduced amount of DS and an increase in CS in fibroblasts from a patient with a mutation of p.Arg213Pro in CHST14 compared to control subjects [133].
In 2005, Kosho et al. reported two probands with generalized joint laxity, scoliosis, fragility, hyperextensibility, readily bruisable skin, atrophic scars, hypotonia, recurrent hematomas, pectus excavatum, and a mild delay of gross motor development [138]. In view of these features, they proposed probands with EDS kyphoscoliosis type VIB. In 2010, Kosho et al. reported six unrelated patients with EDS characterized by progressive multisystem fragility, spinal deformities, recurrent dislocations, progressive skin and joint laxities, multiple congenital contracture of the joints, and characteristic craniofacial features [139]. Subsequently, Miyake et al. identified mutations in CHST14 encoding D4ST-1 in six probands [140]. The compound heterozygous mutations p.Lys69*/p.Pro281Leu, p.Pro281Leu/p.Cys289Ser, and p.Pro281Leu/p.Tyr293Cys or homozygous mutation p.Pro281Leu were identified in these probands. The recombinant CHST14/D4ST-1 mutants p.Pro281Leu, p.Cys289Ser, and p.Tyr293Cys, which were expressed by COS-7 cells, showed markedly lower D4ST activity than the recombinant wild-type [140]. Consistent with this finding, skin fibroblast cultures from patients with the mutation p.Pro281Leu or p.Pro281Leu/p.Tyr293Cys also showed considerably weaker D4ST activity than healthy subjects [140]. Thus, these substitutions of amino acids affected the enzymatic activity of D4ST-1. Instead of dermatan, a CS chain was produced on the decorin core protein of skin fibroblasts from patients [140]. Because 4-O-sulfation in DS inhibits the enzymatic reaction of the conversion of IdoUA into GlcUA by DSE, the lack of 4-O-sulfation in DS side chains in probands causes the reverse epimerization reaction, the conversion of IdoUA to GlcUA in dermatan by DSE, resulting in the re-formation of chondroitin, which is sulfated by C4ST to form CS.
In 2019, Hirose et al. demonstrated the skin pathology of probands with the musculocontractural type of EDS, with both transmission electron microscopy-based cupromeronic blue staining to detect GAG chains and immunostaining of decorin [141]. Collagen fibrils were tightly and regularly assembled in controls; in contrast, they were dispersed in the affected papillary to reticular dermis. Moreover, DS side chains of decorin-PG from control subjects were curved, maintaining close contact with attached collagen fibrils, whereas affected GAGs, CS side chains of decorin-PGs, were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils. These findings suggest that structural alterations of GAG side chains on decorin-PG lead to spatial disorganization of collagen networks. In 2017, Mizumoto et al. demonstrated the absence of urinary DS in patients with pathogenic variants in CHST14/D4ST1 by an anion-exchange HPLC in conjugation with the DS-degrading enzyme chondroitinase B [142]. This method indicates the usefulness of urinary disaccharide compositional analysis of DS chains as non-invasive screening for this disorder.
In 2010, Malfait et al. also independently reported that EDS kyphoscoliotic type VIB in three probands from two families was caused by the homozygous mutations p.Val49* and p.Glu334Glyfs*107 in CHST14 [143]. They proposed to unify the D4ST1-related syndromes, the novel EDS and the adducted thumb–clubfoot syndrome, as ‘‘musculocontractural EDS’’ [143], which was adopted in the International Classification of Ehlers–Danlos Syndromes in 2017 as EDS musculocontractural type 1 [144,145]. In addition to these mutations in CHST14, many probands with EDS musculocontractural type 1 have been reported to date [146,147,148,149,150,151,152,153,154,155,156,157,158,159].

4. Conclusions

Recent studies on in vivo functions of DSE, DSEL/DSE2, and CHST14/D4ST-1 using their knockout mice and human cells from patients have partially clarified the pathogenic mechanisms of the disorder as well as the biological significance of DS side chains of DS-PGs. These findings are due to marked contributions by a large number of basic studies since the 1970s by glycobiologists, biochemists, clinicians, and geneticists. Additionally, the knockout mice of these genes help further our understanding of the musculocontractural type of EDS. Advancements in our understanding of the molecular mechanisms involving DS may be necessary for the development of therapeutic approaches and agents.

Author Contributions

S.M. wrote the manuscript. S.Y. provided fruitful comments. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported in part by a Grant-in Aid for Scientific Research (C) from the Japan Society for the Promotion of Science, Japan (19K07054 to S.M.; 21K06552 to S.Y.) and a Grant-in Aid for the Research Center for Pathogenesis of Intractable Diseases from the Research Institute of Meijo University (S.M. and S.Y.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Fransson, L.-A.; Cheng, F.; Yoshida, K.; Heinegård, D.; Malmström, A.; Schmidtchen, A. Patterns of epimerization and sulphation in dermatan sulphate chains. In Dermatan Sulphate Proteoglycans: Chemistry, Biology, Chemical Pathology; Scott, J.E., Ed.; Portland Press: London, UK, 1993; pp. 11–25. [Google Scholar]
  2. Trowbridge, J.M.; Gallo, R.L. Dermatan sulfate: New functions from an old glycosaminoglycan. Glycobiology 2002, 12, 117R–125R. [Google Scholar] [CrossRef] [PubMed]
  3. Thelin, M.A.; Bartolini, B.; Axelsson, J.; Gustafsson, R.; Tykesson, E.; Pera, E.; Oldberg, Å.; Maccarana, M.; Malmström, A. Biological functions of iduronic acid in chondroitin/dermatan sulfate. FEBS J. 2013, 280, 2431–2446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Mizumoto, S.; Yamada, S. The specific role of dermatan sulfate as an instructive glycosaminoglycan in tissue development. Int. J. Mol. Sci. 2022, 23, 7485. [Google Scholar] [CrossRef] [PubMed]
  5. Mizumoto, S.; Kosho, T.; Yamada, S.; Sugahara, K. Pathophysiological significance of dermatan sulfate proteoglycans revealed by human genetic disorders. Pharmaceuticals 2017, 10, 34. [Google Scholar] [CrossRef] [Green Version]
  6. Karl, M.; Chaffee, E. The mucopolysaccharides of skin. J. Biol. Chem. 1941, 138, 491–499. [Google Scholar]
  7. Anderson, J.C. Isolation of a glycoprotein and proteodermatan sulphate from bovine achilles tendon by affinity chromatography on concanavalin A-Sepharose. Biochim. Biophys. Acta 1975, 379, 444–455. [Google Scholar] [CrossRef]
  8. Cöster, L.; Fransson, L.A. Isolation and characterization of dermatan sulphate proteoglycans from bovine sclera. Biochem. J. 1981, 193, 143–153. [Google Scholar] [CrossRef] [Green Version]
  9. Damle, S.P.; Cöster, L.; Gregory, J.D. Proteodermatan sulfate isolated from pig skin. J. Biol. Chem. 1982, 257, 5523–5527. [Google Scholar] [CrossRef]
  10. Fujii, N.; Nagai, Y. Isolation and characterization of a proteodermatan sulfate from calf skin. J. Biochem. 1981, 90, 1249–1258. [Google Scholar] [CrossRef]
  11. Pearson, C.H.; Gibson, G.J. Proteoglycans of bovine periodontal ligament and skin. Occurrence of different hybrid-sulphated galactosaminoglycans in distinct proteoglycans. Biochem. J. 1982, 201, 27–37. [Google Scholar] [CrossRef] [Green Version]
  12. Rosenberg, L.C.; Choi, H.U.; Tang, L.H.; Johnson, T.L.; Pal, S.; Webber, C.; Reiner, A.; Poole, A.R. Isolation of dermatan sulfate proteoglycans from mature bovine articular cartilages. J. Biol. Chem. 1985, 260, 6304–63013. [Google Scholar] [CrossRef]
  13. Krusius, T.; Ruoslahti, E. Primary structure of an extracellular matrix proteoglycan core protein deduced from cloned cDNA. Proc. Natl. Acad. Sci. USA 1986, 83, 7683–7687. [Google Scholar] [CrossRef] [Green Version]
  14. Day, A.A.; McQuillan, C.I.; Termine, J.D.; Young, M.R. Molecular cloning and sequence analysis of the cDNA for small proteoglycan II of bovine bone. Biochem. J. 1987, 248, 801–805. [Google Scholar] [CrossRef]
  15. Li, W.; Vergnes, J.P.; Cornuet, P.K.; Hassell, J.R. cDNA clone to chick corneal chondroitin/dermatan sulfate proteoglycan reveals identity to decorin. Arch. Biochem. Biophys. 1992, 296, 190–197. [Google Scholar] [CrossRef]
  16. Abramson, S.R.; Woessner, J.F., Jr. cDNA sequence for rat dermatan sulfate proteoglycan-II (decorin). Biochim. Biophys. Acta 1992, 1132, 225–227. [Google Scholar] [CrossRef]
  17. Fisher, L.W.; Termine, J.D.; Young, M.F. Deduced protein sequence of bone small proteoglycan I (biglycan) shows homology with proteoglycan II (decorin) and several nonconnective tissue proteins in a variety of species. J. Biol. Chem. 1989, 264, 4571–4576. [Google Scholar] [CrossRef]
  18. Neame, P.J.; Choi, H.U.; Rosenberg, L.C. The primary structure of the core protein of the small, leucine-rich proteoglycan (PG I) from bovine articular cartilage. J. Biol. Chem. 1989, 264, 8653–86561. [Google Scholar] [CrossRef]
  19. Shinomura, T.; Kimata, K. Proteoglycan-Lb, a small dermatan sulfate proteoglycan expressed in embryonic chick epiphyseal cartilage, is structurally related to osteoinductive factor. J. Biol. Chem. 1992, 267, 1265–1270. [Google Scholar] [CrossRef]
  20. Lassalle, P.; Molet, S.; Janin, A.; Heyden, J.V.; Tavernier, J.; Fiers, W.; Devos, R.; Tonnel, A.B. ESM-1 is a novel human endothelial cell-specific molecule expressed in lung and regulated by cytokines. J. Biol. Chem. 1996, 271, 20458–20464. [Google Scholar] [CrossRef] [Green Version]
  21. Béchard, D.; Gentina, T.; Delehedde, M.; Scherpereel, A.; Lyon, M.; Aumercier, M.; Vazeux, R.; Richet, C.; Degand, P.; Jude, B.; et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J. Biol. Chem. 2001, 276, 48341–48349. [Google Scholar] [CrossRef] [Green Version]
  22. Bella, A., Jr.; Danishefsky, I. The dermatan sulfate-protein linkage region. J. Biol. Chem. 1968, 243, 2660–2664. [Google Scholar] [CrossRef] [PubMed]
  23. Fransson, L.A. Structure of dermatan sulfate. IV. Glycopeptides from the carbohydrate-protein linkage region of pig skin dermatan sulfate. Biochim. Biophys. Acta 1968, 156, 311–316. [Google Scholar] [CrossRef] [PubMed]
  24. Stern, E.L.; Lindahl, B.; Rodén, L. The linkage of dermatan sulfate to protein. II. Monosaccharide sequence of the linkage region. J. Biol. Chem. 1971, 246, 5707–5715. [Google Scholar] [CrossRef] [PubMed]
  25. Sugahara, K.; Ohkita, Y.; Shibata, Y.; Yoshida, K.; Ikegami, A. Structural studies on the hexasaccharide alditols isolated from the carbohydrate-protein linkage region of dermatan sulfate proteoglycans of bovine aorta: Demonstration of iduronic acid-containing components. J. Biol. Chem. 1995, 270, 7204–7212. [Google Scholar] [CrossRef] [Green Version]
  26. Lindahl, U.; Rodén, L. The chondroitin 4-sulfate-protein linkage. J. Biol. Chem. 1966, 241, 2113–2119. [Google Scholar] [CrossRef]
  27. Lindahl, U.; Rodén, L. Carbohydrate-protein linkages in proteoglycans of animal, plant and bacterial origin. In Glycoproteins: Their Composition, Structure and Function; Gottschalk, A., Ed.; Elsevier: Amsterdam, The Netherlands, 1972; pp. 491–517. [Google Scholar]
  28. Kjellén, L.; Lindahl, U. Proteoglycans: Structures and interactions. Annu. Rev. Biochem. 1991, 60, 443–475. [Google Scholar] [CrossRef]
  29. Iozzo, R.V. Matrix proteoglycans: From molecular design to cellular function. Annu. Rev. Biochem. 1998, 67, 609–652. [Google Scholar] [CrossRef] [Green Version]
  30. Karamanos, N.K.; Piperigkou, Z.; Theocharis, A.D.; Watanabe, H.; Franchi, M.; Baud, S.; Brézillon, S.; Götte, M.; Passi, A.; Vigetti, D.; et al. Proteoglycan chemical diversity drives multifunctional cell regulation and therapeutics. Chem. Rev. 2018, 118, 9152–9232. [Google Scholar] [CrossRef]
  31. Diehl, V.; Huber, L.S.; Trebicka, J.; Wygrecka, M.; Iozzo, R.V.; Schaefer, L. The role of decorin and biglycan signaling in tumorigenesis. Front. Oncol. 2021, 11, 801801. [Google Scholar] [CrossRef]
  32. Sugahara, K.; Mikami, T.; Uyama, T.; Mizuguchi, S.; Nomura, K.; Kitagawa, H. Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr. Opin. Struct. Biol. 2003, 13, 612–620. [Google Scholar] [CrossRef]
  33. Sugahara, K.; Mikami, T. Chondroitin/dermatan sulfate in the central nervous system. Curr. Opin. Struct. Biol. 2007, 17, 536–545. [Google Scholar] [CrossRef]
  34. Mizumoto, S.; Yamada, S.; Sugahara, K. Molecular interactions between chondroitin-dermatan sulfate and growth factors/receptors/matrix proteins. Curr. Opin. Struct. Biol. 2015, 34, 35–42. [Google Scholar] [CrossRef]
  35. Hayes, A.J.; Melrose, J. Neural tissue homeostasis and repair is regulated via CS and DS proteoglycan motifs. Front. Cell Dev. Biol. 2021, 9, 696640. [Google Scholar] [CrossRef]
  36. Grebner, E.E.; Hall, C.W.; Neufeld, E.F. Glycosylation of serine residues by a uridine diphosphate-xylose: Protein xylosyltransferase from mouse mastocytoma. Arch. Biochem. Biophys. 1966, 116, 391–398. [Google Scholar] [CrossRef]
  37. Robinson, H.C.; Telser, A.; Dorfman, A. Studies on biosynthesis of the linkage region of chondroitin sulfate-protein complex. Proc. Natl. Acad. Sci. USA 1966, 56, 1859–1866. [Google Scholar] [CrossRef] [Green Version]
  38. Schwartz, N.B.; Rodén, L. Biosynthesis of chondroitin sulfate. Purification of UDP-D-xylose:core protein β-D-xylosyltransferase by affinity chromatography. Carbohydr. Res. 1974, 37, 167–180. [Google Scholar] [CrossRef]
  39. Schwartz, N.B.; Dorfman, A. Purification of rat chondrosarcoma xylosyltransferase. Arch. Biochem. Biophys. 1975, 171, 136–144. [Google Scholar] [CrossRef]
  40. Kuhn, J.; Götting, C.; Schnölzer, M.; Kempf, T.; Brinkmann, T.; Kleesiek, K. First isolation of human UDP-D-xylose: Proteoglycan core protein β-D-xylosyltransferase secreted from cultured JAR choriocarcinoma cells. J. Biol. Chem. 2001, 276, 4940–4947. [Google Scholar] [CrossRef] [Green Version]
  41. Götting, C.; Kuhn, J.; Zahn, R.; Brinkmann, T.; Kleesiek, K. Molecular cloning and expression of human UDP-D-Xylose:proteoglycan core protein β-D-xylosyltransferase and its first isoform XT-II. J. Mol. Biol. 2000, 304, 517–528. [Google Scholar] [CrossRef]
  42. Pönighaus, C.; Ambrosius, M.; Casanova, J.C.; Prante, C.; Kuhn, J.; Esko, J.D.; Kleesiek, K.; Götting, C. Human xylosyltransferase II is involved in the biosynthesis of the uniform tetrasaccharide linkage region in chondroitin sulfate and heparan sulfate proteoglycans. J. Biol. Chem. 2007, 282, 5201–5206. [Google Scholar] [CrossRef] [Green Version]
  43. Voglmeir, J.; Voglauer, R.; Wilson, I.B. XT-II, the second isoform of human peptide-O-xylosyltransferase, displays enzymatic activity. J. Biol. Chem. 2007, 282, 5984–5990. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Schön, S.; Prante, C.; Bahr, C.; Kuhn, J.; Kleesiek, K.; Götting, C. Cloning and recombinant expression of active full-length xylosyltransferase I (XT-I) and characterization of subcellular localization of XT-I and XT-II. J. Biol. Chem. 2006, 281, 14224–14231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Helting, T.; Rodén, L. Biosynthesis of chondroitin sulfate. I. Galactosyl transfer in the formation of the carbohydrate-protein linkage region. J. Biol. Chem. 1969, 244, 2790–2798. [Google Scholar] [CrossRef] [PubMed]
  46. Schwartz, N.B.; Rodén, L. Biosynthesis of chondroitin sulfate. Solubilization of chondroitin sulfate glycosyltransferases and partial purification of uridine diphosphate-D-galactose:D-xylose galactosyltrans. J. Biol. Chem. 1975, 250, 5200–5207. [Google Scholar] [CrossRef] [PubMed]
  47. Okajima, T.; Yoshida, K.; Kondo, T.; Furukawa, K. Human homolog of Caenorhabditis elegans sqv-3 gene is galactosyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans. J. Biol. Chem. 1999, 274, 22915–22918. [Google Scholar] [CrossRef] [Green Version]
  48. Almeida, R.; Levery, S.B.; Mandel, U.; Kresse, H.; Schwientek, T.; Bennett, E.P.; Clausen, H. Cloning and expression of a proteoglycan UDP-galactose:β-xylose beta1,4-galactosyltransferase I. A seventh member of the human beta4-galactosyltransferase gene family. J. Biol. Chem. 1999, 274, 26165–26171. [Google Scholar] [CrossRef] [Green Version]
  49. Okajima, T.; Fukumoto, S.; Furukawa, K.; Urano, T. Molecular basis for the progeroid variant of Ehlers-Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene. J. Biol. Chem. 1999, 274, 28841–28844. [Google Scholar] [CrossRef] [Green Version]
  50. Schwartz, N.B.; Rodén, L.; Dorfman, A. Biosynthesis of chondroitin sulfate: Interaction between xylosyltransferase and galactosyltransferase. Biochem. Biophys. Res. Commun. 1974, 56, 717–724. [Google Scholar] [CrossRef]
  51. Schwartz, N.B. Biosynthesis of chondroitin sulfate: Immunoprecipitation of interacting xylosyltransferase and galactosyltransferase. FEBS Lett. 1975, 49, 342–345. [Google Scholar] [CrossRef] [Green Version]
  52. Bai, X.; Zhou, D.; Brown, J.R.; Crawford, B.E.; Hennet, T.; Esko, J.D. Biosynthesis of the linkage region of glycosaminoglycans: Cloning and activity of galactosyltransferase II, the sixth member of the β1,3-galactosyltransferase family (beta3GalT6). J. Biol. Chem. 2001, 276, 48189–48195. [Google Scholar] [CrossRef] [Green Version]
  53. Helting, T.; Rodén, L. Biosynthesis of chondroitin sulfate. II. Glucuronosyl transfer in the formation of the carbohydrate-protein linkage region. J. Biol. Chem. 1969, 244, 2799–2805. [Google Scholar] [CrossRef]
  54. Brandt, A.E.; Distler, J.; Jourdian, G.W. Biosynthesis of the chondroitin sulfate-protein linkage region: Purification and properties of a glucuronosyltransferase from embryonic chick brain. Proc. Natl. Acad. Sci. USA 1969, 64, 374–380. [Google Scholar] [CrossRef] [Green Version]
  55. Helting, T. Biosynthesis of heparin. Solubilization and partial purification of uridine diphosphate glucuronic acid: Acceptor glucuronosyltransferase from mouse mastocytoma. J. Biol. Chem. 1972, 247, 4327–4332. [Google Scholar] [CrossRef]
  56. Kitagawa, H.; Tone, Y.; Tamura, J.; Neumann, K.W.; Ogawa, T.; Oka, S.; Kawasaki, T.; Sugahara, K. Molecular cloning and expression of glucuronyltransferase I involved in the biosynthesis of the glycosaminoglycan-protein linkage region of proteoglycans. J. Biol. Chem. 1998, 273, 6615–6618. [Google Scholar] [CrossRef] [Green Version]
  57. Wei, G.; Bai, X.; Sarkar, A.K.; Esko, J.D. Formation of HNK-1 determinants and the glycosaminoglycan tetrasaccharide linkage region by UDP-GlcUA:Galactose beta1, 3-glucuronosyltransferases. J. Biol. Chem. 1999, 274, 7857–7864. [Google Scholar] [CrossRef] [Green Version]
  58. Rohrmann, K.; Niemann, R.; Buddecke, E. Two N-acetylgalactosaminyltransferase are involved in the biosynthesis of chondroitin sulfate. Eur. J. Biochem. 1985, 148, 463–469. [Google Scholar] [CrossRef]
  59. Lidholt, K.; Fjelstad, M.; Lindahl, U.; Goto, F.; Ogawa, T.; Kitagawa, H.; Sugahara, K. Assessment of glycosaminoglycan-protein linkage tetrasaccharides as acceptors for GalNAc- and GlcNAc-transferases from mouse mastocytoma. Glycoconj. J. 1997, 14, 737–742. [Google Scholar] [CrossRef]
  60. Nadanaka, S.; Kitagawa, H.; Goto, F.; Tamura, J.; Neumann, K.W.; Ogawa, T.; Sugahara, K. Involvement of the core protein in the first β-N-acetylgalactosamine transfer to the glycosaminoglycan-protein linkage-region tetrasaccharide and in the subsequent polymerization: The critical determining step for chondroitin sulphate biosynthesis. Biochem. J. 1999, 340, 353–357. [Google Scholar] [CrossRef]
  61. Uyama, T.; Kitagawa, H.; Tamura, J.; Sugahara, K. Molecular cloning and expression of human chondroitin N-acetylgalactosaminyltransferase: The key enzyme for chain initiation and elongation of chondroitin/dermatan sulfate on the protein linkage region tetrasaccharide shared by heparin/heparan sulfate. J. Biol. Chem. 2002, 277, 8841–8846. [Google Scholar] [CrossRef] [Green Version]
  62. Gotoh, M.; Sato, T.; Akashima, T.; Iwasaki, H.; Kameyama, A.; Mochizuki, H.; Yada, T.; Inaba, N.; Zhang, Y.; Kikuchi, N.; et al. Enzymatic synthesis of chondroitin with a novel chondroitin sulfate N-acetylgalactosaminyltransferase that transfers N-acetylgalactosamine to glucuronic acid in initiation and elongation of chondroitin sulfate synthesis. J. Biol. Chem. 2002, 277, 38189–38196. [Google Scholar] [CrossRef] [Green Version]
  63. Uyama, T.; Kitagawa, H.; Tanaka, J.; Tamura, J.; Ogawa, T.; Sugahara, K. Molecular cloning and expression of a second chondroitin N-acetylgalactosaminyltransferase involved in the initiation and elongation of chondroitin/dermatan sulfate. J. Biol. Chem. 2003, 278, 3072–3078. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Sato, T.; Gotoh, M.; Kiyohara, K.; Akashima, T.; Iwasaki, H.; Kameyama, A.; Mochizuki, H.; Yada, T.; Inaba, N.; Togayachi, A.; et al. Differential roles of two N-acetylgalactosaminyltransferases, CSGalNAcT-1, and a novel enzyme, CSGalNAcT-2. Initiation and elongation in synthesis of chondroitin sulfate. J. Biol. Chem. 2003, 278, 3063–3071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Perlman, R.L.; Telser, A.; Dorfman, A. The biosynthesis of chondroitin sulfate by a cell-free preparation. J. Biol. Chem. 1964, 239, 3623–3629. [Google Scholar] [CrossRef] [PubMed]
  66. Silbert, J.E. Incorporation of 14C and 3H from labeled nucleotide sugars into a polysaccharide in the presence of a cell-free preparation from cartilage. J. Biol. Chem. 1964, 239, 1310–1315. [Google Scholar] [CrossRef] [PubMed]
  67. Telser, A.; Robinson, H.C.; Dorfman, A. The biosynthesis of chondroitin sulfate. Arch. Biochem. Biophys. 1966, 116, 458–465. [Google Scholar] [CrossRef]
  68. Dorfman, A. Adventures in viscous solutions. Mol. Cell. Biochem. 1974, 4, 45–74. [Google Scholar] [CrossRef]
  69. Silbert, J.E.; Reppucci, A.C., Jr. Biosynthesis of chondroitin sulfate. Independent addition of glucuronic acid and N-acetylgalactosamine to oligosaccharides. J. Biol. Chem. 1976, 251, 3942–3947. [Google Scholar] [CrossRef]
  70. Kitagawa, H.; Ujikawa, M.; Tsutsumi, K.; Tamura, J.; Neumann, K.W.; Ogawa, T.; Sugahara, K. Characterization of serum β-glucuronyltransferase involved in chondroitin sulfate biosynthesis. Glycobiology 1997, 7, 905–911. [Google Scholar] [CrossRef] [Green Version]
  71. Kitagawa, H.; Tsuchida, K.; Ujikawa, M.; Sugahara, K. Detection and characterization of UDP-GalNAc: Chondroitin N-acetylgalactosaminyltransferase in bovine serum using a simple assay method. J. Biochem. 1995, 117, 1083–1087. [Google Scholar] [CrossRef]
  72. Kitagawa, H.; Tsutsumi, K.; Ujikawa, M.; Goto, F.; Tamura, J.; Neumann, K.W.; Ogawa, T.; Sugahara, K. Regulation of chondroitin sulfate biosynthesis by specific sulfation: Acceptor specificity of serum β-GalNAc transferase revealed by structurally defined oligosaccharides. Glycobiology 1997, 7, 531–537. [Google Scholar] [CrossRef]
  73. Kitagawa, H.; Uyama, T.; Sugahara, K. Molecular cloning and expression of a human chondroitin synthase. J. Biol. Chem. 2001, 276, 38721–38726. [Google Scholar] [CrossRef] [Green Version]
  74. Kitagawa, H.; Izumikawa, T.; Uyama, T.; Sugahara, K. Molecular cloning of a chondroitin polymerizing factor that cooperates with chondroitin synthase for chondroitin polymerization. J. Biol. Chem. 2003, 278, 23666–23671. [Google Scholar] [CrossRef] [Green Version]
  75. Yada, T.; Gotoh, M.; Sato, T.; Shionyu, M.; Go, M.; Kaseyama, H.; Iwasaki, H.; Kikuchi, N.; Kwon, Y.D.; Togayachi, A.; et al. Chondroitin sulfate synthase-2. Molecular cloning and characterization of a novel human glycosyltransferase homologous to chondroitin sulfate glucuronyltransferase, which has dual enzymatic activities. J. Biol. Chem. 2003, 278, 30235–30247. [Google Scholar] [CrossRef] [Green Version]
  76. Izumikawa, T.; Uyama, T.; Okuura, Y.; Sugahara, K.; Kitagawa, H. Involvement of chondroitin sulfate synthase-3 (chondroitin synthase-2) in chondroitin polymerization through its interaction with chondroitin synthase-1 or chondroitin polymerizing factor. Biochem. J. 2007, 403, 545–552. [Google Scholar] [CrossRef]
  77. Yada, T.; Sato, T.; Kaseyama, H.; Gotoh, M.; Iwasaki, H.; Kikuchi, N.; Kwon, Y.D.; Togayachi, A.; Kudo, T.; Watanabe, H.; et al. Chondroitin sulfate synthase-3. Molecular cloning and characterization. J. Biol. Chem. 2003, 278, 39711–39725. [Google Scholar] [CrossRef] [Green Version]
  78. Izumikawa, T.; Koike, T.; Shiozawa, S.; Sugahara, K.; Tamura, J.; Kitagawa, H. Identification of chondroitin sulfate glucuronyltransferase as chondroitin synthase-3 involved in chondroitin polymerization: Chondroitin polymerization is achieved by multiple enzyme complexes consisting of chondroitin synthase family members. J. Biol. Chem. 2008, 283, 11396–11406. [Google Scholar] [CrossRef] [Green Version]
  79. Gotoh, M.; Yada, T.; Sato, T.; Akashima, T.; Iwasaki, H.; Mochizuki, H.; Inaba, N.; Togayachi, A.; Kudo, T.; Watanabe, H.; et al. Molecular cloning and characterization of a novel chondroitin sulfate glucuronyltransferase that transfers glucuronic acid to N-acetylgalactosamine. J. Biol. Chem. 2002, 277, 38179–38188. [Google Scholar] [CrossRef] [Green Version]
  80. Malmström, A.; Fransson, L.A. Biosynthesis of dermatan sulfate. I. Formation of L-iduronic acid residues. J. Biol. Chem. 1975, 250, 3419–3425. [Google Scholar] [CrossRef]
  81. Malmström, A. Biosynthesis of dermatan sulphate. Loss of C-5 hydrogen during conversion of D-glucuronate to L-iduronate. Biochem. J. 1981, 198, 669–675. [Google Scholar] [CrossRef] [Green Version]
  82. Malmström, A.; Aberg, L. Biosynthesis of dermatan sulphate. Assay and properties of the uronosyl C-5 epimerase. Biochem. J. 1982, 201, 489–493. [Google Scholar] [CrossRef] [Green Version]
  83. Malmström, A. Biosynthesis of dermatan sulfate. II. Substrate specificity of the C-5 uronosyl epimerase. J. Biol. Chem. 1984, 259, 161–165. [Google Scholar] [CrossRef]
  84. Campbell, P.; Feingold, D.S.; Jensen, J.W.; Malmström, A.; Rodén, L. New assay for uronosyl 5-epimerases. Anal. Biochem. 1983, 131, 46–52. [Google Scholar] [CrossRef] [PubMed]
  85. Cöster, L.; Hernnäs, J.; Malmström, A. Biosynthesis of dermatan sulphate proteoglycans. The effect of β-D-xyloside addition on the polymer-modification process in fibroblast cultures. Biochem. J. 1991, 276, 533–539. [Google Scholar] [CrossRef] [PubMed]
  86. Hannesson, H.H.; Hagner-McWhirter, A.; Tiedemann, K.; Lindahl, U.; Malmström, A. Biosynthesis of dermatan sulphate. Defructosylated Escherichia coli K4 capsular polysaccharide as a substrate for the D-glucuronyl C-5 epimerase, and an indication of a two-base reaction mechanism. Biochem. J. 1996, 313, 589–596. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Tiedemann, K.; Larsson, T.; Heinegård, D.; Malmström, A. The glucuronyl C5-epimerase activity is the limiting factor in the dermatan sulfate biosynthesis. Arch. Biochem. Biophys. 2001, 391, 65–71. [Google Scholar] [CrossRef]
  88. Maccarana, M.; Olander, B.; Malmström, J.; Tiedemann, K.; Aebersold, R.; Lindahl, U.; Li, J.P.; Malmström, A. Biosynthesis of dermatan sulfate: Chondroitin-glucuronate C5-epimerase is identical to SART2. J. Biol. Chem. 2006, 281, 11560–11568. [Google Scholar] [CrossRef] [Green Version]
  89. Pacheco, B.; Maccarana, M.; Goodlett, D.R.; Malmström, A.; Malmström, L. Identification of the active site of DS-epimerase 1 and requirement of N-glycosylation for enzyme function. J. Biol. Chem. 2009, 284, 1741–1747. [Google Scholar] [CrossRef] [Green Version]
  90. Pacheco, B.; Malmström, A.; Maccarana, M. Two dermatan sulfate epimerases form iduronic acid domains in dermatan sulfate. J. Biol. Chem. 2009, 284, 9788–9795. [Google Scholar] [CrossRef] [Green Version]
  91. Nakao, M.; Shichijo, S.; Imaizumi, T.; Inoue, Y.; Matsunaga, K.; Yamada, A.; Kikuchi, M.; Tsuda, N.; Ohta, K.; Takamori, S.; et al. Identification of a gene coding for a new squamous cell carcinoma antigen recognized by the CTL. J. Immunol. 2000, 164, 2565–2574. [Google Scholar] [CrossRef] [Green Version]
  92. Goossens, D.; Van Gestel, S.; Claes, S.; De Rijk, P.; Souery, D.; Massat, I.; Van den Bossche, D.; Backhovens, H.; Mendlewicz, J.; Van Broeckhoven, C.; et al. A novel CpG-associated brain-expressed candidate gene for chromosome 18q-linked bipolar disorder. Mol. Psychiatry 2003, 8, 83–89. [Google Scholar] [CrossRef] [Green Version]
  93. Eklund, E.; Rodén, L.; Malmström, M.; Malmström, A. Dermatan is a better substrate for 4-O-sulfation than chondroitin: Implications in the generation of 4-O-sulfated, L-iduronate-rich galactosaminoglycans. Arch. Biochem. Biophys. 2000, 383, 171–177. [Google Scholar] [CrossRef]
  94. Evers, M.R.; Xia, G.; Kang, H.G.; Schachner, M.; Baenziger, J.U. Molecular cloning and characterization of a dermatan-specific N-acetylgalactosamine 4-O-sulfotransferase. J. Biol. Chem. 2001, 276, 36344–36353. [Google Scholar] [CrossRef] [Green Version]
  95. Mikami, T.; Mizumoto, S.; Kago, N.; Kitagawa, H.; Sugahara, K. Specificities of three distinct human chondroitin/dermatan N-acetylgalactosamine 4-O-sulfotransferases demonstrated using partially desulfated dermatan sulfate as an acceptor: Implication of differential roles in dermatan sulfate biosynthesis. J. Biol. Chem. 2003, 278, 36115–36127. [Google Scholar] [CrossRef] [Green Version]
  96. Pacheco, B.; Maccarana, M.; Malmström, A. Dermatan 4-O-sulfotransferase 1 is pivotal in the formation of iduronic acid blocks in dermatan sulfate. Glycobiology 2009, 19, 1197–1203. [Google Scholar] [CrossRef] [Green Version]
  97. Kobayashi, M.; Sugumaran, G.; Liu, J.; Shworak, N.W.; Silbert, J.E.; Rosenberg, R.D. Molecular cloning and characterization of a human uronyl 2-sulfotransferase that sulfates iduronyl and glucuronyl residues in dermatan/chondroitin sulfate. J. Biol. Chem. 1999, 274, 10474–10480. [Google Scholar] [CrossRef] [Green Version]
  98. Ohtake, S.; Kimata, K.; Habuchi, O. Recognition of sulfation pattern of chondroitin sulfate by uronosyl 2-O-sulfotransferase. J. Biol. Chem. 2005, 280, 39115–39123. [Google Scholar] [CrossRef] [Green Version]
  99. Yamada, S.; Van Die, I.; Van den Eijnden, D.H.; Yokota, A.; Kitagawa, H.; Sugahara, K. Demonstration of glycosaminoglycans in Caenorhabditis elegans. FEBS Lett. 1999, 459, 327–331. [Google Scholar] [CrossRef] [Green Version]
  100. Toyoda, H.; Kinoshita-Toyoda, A.; Selleck, S.B. Structural analysis of glycosaminoglycans in Drosophila and Caenorhabditis elegans and demonstration that tout-velu, a Drosophila gene related to EXT tumor suppressors, affects heparan sulfate in vivo. J. Biol. Chem. 2000, 275, 2269–2275. [Google Scholar] [CrossRef] [Green Version]
  101. Yamada, S.; Okada, Y.; Ueno, M.; Iwata, S.; Deepa, S.S.; Nishimura, S.; Fujita, M.; Van Die, I.; Hirabayashi, Y.; Sugahara, K. Determination of the glycosaminoglycan-protein linkage region oligosaccharide structures of proteoglycans from Drosophila melanogaster and Caenorhabditis elegans. J. Biol. Chem. 2002, 277, 31877–31886. [Google Scholar] [CrossRef] [Green Version]
  102. Maccarana, M.; Kalamajski, S.; Kongsgaard, M.; Magnusson, S.P.; Oldberg, A.; Malmström, A. Dermatan sulfate epimerase 1-deficient mice have reduced content and changed distribution of iduronic acids in dermatan sulfate and an altered collagen structure in skin. Mol. Cell. Biol. 2009, 29, 5517–5528. [Google Scholar] [CrossRef] [Green Version]
  103. Bartolini, B.; Thelin, M.A.; Svensson, L.; Ghiselli, G.; van Kuppevelt, T.H.; Malmström, A.; Maccarana, M. Iduronic acid in chondroitin/dermatan sulfate affects directional migration of aortic smooth muscle cells. PLoS ONE 2013, 8, e66704. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Gustafsson, R.; Stachtea, X.; Maccarana, M.; Grottling, E.; Eklund, E.; Malmström, A.; Oldberg, A. Dermatan sulfate epimerase 1 deficient mice as a model for human abdominal wall defects. Birth Defects Res. A Clin. Mol. Teratol. 2014, 100, 712–720. [Google Scholar] [CrossRef] [Green Version]
  105. Nadafi, R.; Koning, J.J.; Veninga, H.; Stachtea, X.N.; Konijn, T.; Zwiers, A.; Malmström, A.; den Haan, J.M.M.; Mebius, R.E.; Maccarana, M.; et al. Dendritic cell migration to skin-draining lymph nodes is controlled by dermatan sulfate and determines adaptive immunity magnitude. Front. Immunol. 2018, 9, 206. [Google Scholar] [CrossRef] [Green Version]
  106. Gouignard, N.; Maccarana, M.; Strate, I.; von Stedingk, K.; Malmström, A.; Pera, E.M. Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: Dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin. Dis. Model Mech. 2016, 9, 607–620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Ten Dam, G.B.; Yamada, S.; Kobayashi, F.; Purushothaman, A.; van de Westerlo, E.M.; Bulten, J.; Malmström, A.; Sugahara, K.; Massuger, L.F.; van Kuppevelt, T.H. Dermatan sulfate domains defined by the novel antibody GD3A12, in normal tissues and ovarian adenocarcinomas. Histochem. Cell. Biol. 2009, 132, 117–127. [Google Scholar] [CrossRef] [PubMed]
  108. Thelin, M.A.; Svensson, K.J.; Shi, X.; Bagher, M.; Axelsson, J.; Isinger-Ekstrand, A.; van Kuppevelt, T.H.; Johansson, J.; Nilbert, M.; Zaia, J.; et al. Dermatan sulfate is involved in the tumorigenic properties of esophagus squamous cell carcinoma. Cancer Res. 2012, 72, 1943–1952. [Google Scholar] [CrossRef] [Green Version]
  109. Müller, T.; Mizumoto, S.; Suresh, I.; Komatsu, Y.; Vodopiutz, J.; Dundar, M.; Straub, V.; Lingenhel, A.; Melmer, A.; Lechner, S.; et al. Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome. Hum. Mol. Genet. 2013, 22, 3761–3772. [Google Scholar] [CrossRef] [Green Version]
  110. Syx, D.; Van Damme, T.; Symoens, S.; Maiburg, M.C.; van de Laar, I.; Morton, J.; Suri, M.; Del Campo, M.; Hausser, I.; Hermanns-Lê, T.; et al. Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis. Hum. Mutat. 2015, 36, 535–547. [Google Scholar] [CrossRef]
  111. Ranza, E.; Huber, C.; Levin, N.; Baujat, G.; Bole-Feysot, C.; Nitschke, P.; Masson, C.; Alanay, Y.; Al-Gazali, L.; Bitoun, P.; et al. Chondrodysplasia with multiple dislocations: Comprehensive study of a series of 30 cases. Clin. Genet. 2017, 91, 868–880. [Google Scholar] [CrossRef]
  112. Schirwani, S.; Metcalfe, K.; Wagner, B.; Berry, I.; Sobey, G.; Jewell, R. DSE associated musculocontractural EDS, a milder phenotype or phenotypic variability. Eur. J. Med. Genet. 2020, 63, 103798. [Google Scholar] [CrossRef]
  113. Lautrup, C.K.; Teik, K.W.; Unzaki, A.; Mizumoto, S.; Syx, D.; Sin, H.H.; Nielsen, I.K.; Markholt, S.; Yamada, S.; Malfait, F.; et al. Delineation of musculocontractural Ehlers-Danlos syndrome caused by dermatan sulfate epimerase deficiency. Mol. Genet. Genom. Med. 2020, 8, e1197. [Google Scholar] [CrossRef] [Green Version]
  114. Akatsu, C.; Mizumoto, S.; Kaneiwa, T.; Maccarana, M.; Malmström, A.; Yamada, S.; Sugahara, K. Dermatan sulfate epimerase 2 is the predominant isozyme in the formation of the chondroitin sulfate/dermatan sulfate hybrid structure in postnatal developing mouse brain. Glycobiology 2011, 21, 565–574. [Google Scholar] [CrossRef] [Green Version]
  115. Bao, X.; Nishimura, S.; Mikami, T.; Yamada, S.; Itoh, N.; Sugahara, K. Chondroitin sulfate/dermatan sulfate hybrid chains from embryonic pig brain, which contain a higher proportion of L-iduronic acid than those from adult pig brain, exhibit neuritogenic and growth factor binding activities. J. Biol. Chem. 2004, 279, 9765–9776. [Google Scholar] [CrossRef] [Green Version]
  116. Mitsunaga, C.; Mikami, T.; Mizumoto, S.; Fukuda, J.; Sugahara, K. Chondroitin sulfate/dermatan sulfate hybrid chains in the development of cerebellum. Spatiotemporal regulation of the expression of critical disulfated disaccharides by specific sulfotransferases. J. Biol. Chem. 2006, 281, 18942–18952. [Google Scholar] [CrossRef] [Green Version]
  117. Bartolini, B.; Thelin, M.A.; Rauch, U.; Feinstein, R.; Oldberg, A.; Malmström, A.; Maccarana, M. Mouse development is not obviously affected by the absence of dermatan sulfate epimerase 2 in spite of a modified brain dermatan sulfate composition. Glycobiology 2021, 22, 1007–1016. [Google Scholar] [CrossRef] [Green Version]
  118. Stachtea, X.N.; Tykesson, E.; van Kuppevelt, T.H.; Feinstein, R.; Malmström, A.; Reijmers, R.M.; Maccarana, M. Dermatan sulfate-free mice display embryological defects and are neonatal lethal despite normal lymphoid and non-lymphoid organogenesis. PLoS ONE 2015, 10, e0140279. [Google Scholar] [CrossRef] [Green Version]
  119. Shi, J.; Potash, J.B.; Knowles, J.A.; Weissman, M.M.; Coryell, W.; Scheftner, W.A.; Lawson, W.B.; DePaulo, J.R., Jr.; Gejman, P.V.; Sanders, A.R.; et al. Genome-wide association study of recurrent early-onset major depressive disorder. Mol. Psychiatry 2011, 16, 193–201. [Google Scholar] [CrossRef] [Green Version]
  120. Zayed, H.; Chao, R.; Moshrefi, A.; Lopezjimenez, N.; Delaney, A.; Chen, J.; Shaw, G.M.; Slavotinek, A.M. A maternally inherited chromosome 18q22.1 deletion in a male with late-presenting diaphragmatic hernia and microphthalmia-evaluation of DSEL as a candidate gene for the diaphragmatic defect. Am. J. Med. Genet. 2010, 152A, 916–923. [Google Scholar] [CrossRef] [Green Version]
  121. Yamauchi, S.; Mita, S.; Matsubara, T.; Fukuta, M.; Habuchi, H.; Kimata, K.; Habuchi, O. Molecular cloning and expression of chondroitin 4-sulfotransferase. J. Biol. Chem. 2000, 275, 8975–8981. [Google Scholar] [CrossRef] [Green Version]
  122. Hiraoka, N.; Nakagawa, H.; Ong, E.; Akama, T.O.; Fukuda, M.N.; Fukuda, M. Molecular cloning and expression of two distinct human chondroitin 4-O-sulfotransferases that belong to the HNK-1 sulfotransferase gene family. J. Biol. Chem. 2000, 75, 20188–20196. [Google Scholar] [CrossRef] [Green Version]
  123. Kang, H.G.; Evers, M.R.; Xia, G.; Baenziger, J.U.; Schachner, M. Molecular cloning and characterization of chondroitin-4-O-sulfotransferase-3. A novel member of the HNK-1 family of sulfotransferases. J. Biol. Chem. 2002, 277, 34766–34772. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Xia, G.; Evers, M.R.; Kang, H.G.; Schachner, M.; Baenziger, J.U. Molecular cloning and expression of the pituitary glycoprotein hormone N-acetylgalactosamine-4-O-sulfotransferase. J. Biol. Chem. 2000, 275, 38402–38409. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Kang, H.G.; Evers, M.R.; Xia, G.; Baenziger, J.U.; Schachner, M. Molecular cloning and expression of an N-acetylgalactosamine-4-O-sulfotransferase that transfers sulfate to terminal and Non-terminal β 1,4-linked N-acetylgalactosamine. J. Biol. Chem. 2001, 276, 10861–10869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Tykesson, E.; Hassinen, A.; Zielinska, K.; Thelin, M.A.; Frati, G.; Ellervik, U.; Westergren-Thorsson, G.; Malmström, A.; Kellokumpu, S.; Maccarana, M. Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks. J. Biol. Chem. 2018, 293, 13725–13735. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Bian, S.; Akyüz, N.; Bernreuther, C.; Loers, G.; Laczynska, E.; Jakovcevski, I.; Schachner, M. Dermatan sulfotransferase Chst14/D4st1, but not chondroitin sulfotransferase Chst11/C4st1, regulates proliferation and neurogenesis of neural progenitor cells. J. Cell Sci. 2011, 124, 4051–4063. [Google Scholar] [CrossRef] [Green Version]
  128. Clement, A.M.; Nadanaka, S.; Masayama, K.; Mandl, C.; Sugahara, K.; Faissner, A. The DSD-1 carbohydrate epitope depends on sulfation, correlates with chondroitin sulfate D motifs, and is sufficient to promote neurite outgrowth. J. Biol. Chem. 1998, 273, 28444–28453. [Google Scholar] [CrossRef] [Green Version]
  129. Ito, Y.; Hikino, M.; Yajima, Y.; Mikami, T.; Sirko, S.; von Holst, A.; Faissner, A.; Fukui, S.; Sugahara, K. Structural characterization of the epitopes of the monoclonal antibodies 473HD, CS-56, and MO-225 specific for chondroitin sulfate D-type using the oligosaccharide library. Glycobiology 2005, 15, 593–603. [Google Scholar] [CrossRef]
  130. von Holst, A.; Sirko, S.; Faissner, A. The unique 473HD-Chondroitinsulfate epitope is expressed by radial glia and involved in neural precursor cell proliferation. J. Neurosci. 2006, 26, 4082–4094. [Google Scholar] [CrossRef] [Green Version]
  131. Akyüz, N.; Rost, S.; Mehanna, A.; Bian, S.; Loers, G.; Oezen, I.; Mishra, B.; Hoffmann, K.; Guseva, D.; Laczynska, E.; et al. Dermatan 4-O-sulfotransferase1 ablation accelerates peripheral nerve regeneration. Exp. Neurol. 2013, 247, 517–530. [Google Scholar] [CrossRef]
  132. Yoshizawa, T.; Mizumoto, S.; Takahashi, Y.; Shimada, S.; Sugahara, K.; Nakayama, J.; Takeda, S.; Nomura, Y.; Nitahara-Kasahara, Y.; Okada, T.; et al. Vascular abnormalities in the placenta of Chst14-/- fetuses: Implications in the pathophysiology of perinatal lethality of the murine model and vascular lesions in human CHST14/D4ST1 deficiency. Glycobiology 2018, 28, 80–89. [Google Scholar] [CrossRef] [Green Version]
  133. Dündar, M.; Müller, T.; Zhang, Q.; Pan, J.; Steinmann, B.; Vodopiutz, J.; Gruber, R.; Sonoda, T.; Krabichler, B.; Utermann, G.; et al. Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome. Am. J. Hum. Genet. 2009, 85, 873–882. [Google Scholar] [CrossRef] [Green Version]
  134. Hirose, T.; Mizumoto, S.; Hashimoto, A.; Takahashi, Y.; Yoshizawa, T.; Nitahara-Kasahara, Y.; Takahashi, N.; Nakayama, J.; Takehana, K.; Okada, T.; et al. 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 2021, 31, 137–150. [Google Scholar] [CrossRef]
  135. Nitahara-Kasahara, Y.; Mizumoto, S.; Inoue, Y.U.; Saka, S.; Posadas-Herrera, G.; Nakamura-Takahashi, A.; Takahashi, Y.; Hashimoto, A.; Konishi, K.; Miyata, S.; et al. Muscle pathophysiology in mouse models of musculocontractural Ehlers-Danlos syndrome due to CHST14 mutations (mcEDS-CHST14), generated through CRISPR/Cas9-mediated genomic editing. Dis. Model. Mech. 2021, 14, dmm048963. [Google Scholar] [CrossRef]
  136. Nitahara-Kasahara, Y.; Posadas-Herrera, G.; Mizumoto, S.; Nakamura-Takahashi, A.; Inoue, Y.U.; Inoue, T.; Nomura, Y.; Takeda, S.; Yamada, S.; Kosho, T.; et al. Myopathy associated with dermatan sulfate-deficient decorin and myostatin in musculocontractural Ehlers-Danlos syndrome: A mouse model investigation. Front. Cell Dev. Biol. 2021, 9, 695021. [Google Scholar] [CrossRef]
  137. Dundar, M.; Demiryilmaz, F.; Demiryilmaz, I.; Kumandas, S.; Erkilic, K.; Kendirci, M.; Tuncel, M.; Ozyazgan, I.; Tolmie, J.L. An autosomal recessive adducted thumb-club foot syndrome observed in Turkish cousins. Clin. Genet. 1997, 51, 61–64. [Google Scholar] [CrossRef]
  138. Kosho, T.; Takahashi, J.; Ohashi, H.; Nishimura, G.; Kato, H.; Fukushima, Y. Ehlers-Danlos syndrome type VIB with characteristic facies, decreased curvatures of the spinal column, and joint contractures in two unrelated girls. Am. J. Med. Genet. A 2005, 138A, 282–287. [Google Scholar] [CrossRef]
  139. Kosho, T.; Miyake, N.; Hatamochi, A.; Takahashi, J.; Kato, H.; Miyahara, T.; Igawa, Y.; Yasui, H.; Ishida, T.; Ono, K.; et al. A new Ehlers-Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. Am. J. Med. Genet. 2010, 152A, 1333–1346. [Google Scholar] [CrossRef]
  140. Miyake, N.; Kosho, T.; Mizumoto, S.; Furuichi, T.; Hatamochi, A.; Nagashima, Y.; Arai, E.; Takahashi, K.; Kawamura, R.; Wakui, K.; et al. Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum. Mutat. 2010, 31, 966–974. [Google Scholar] [CrossRef]
  141. Hirose, T.; Takahashi, N.; Tangkawattana, P.; Minaguchi, J.; Mizumoto, S.; Yamada, S.; Miyake, N.; Hayashi, S.; Hatamochi, A.; Nakayama, J.; et al. Structural alteration of glycosaminoglycan side chains and spatial disorganization of collagen networks in the skin of patients with mcEDS-CHST14. Biochim. Biophys. Acta Gen. Subj. 2019, 1863, 623–631. [Google Scholar] [CrossRef]
  142. Mizumoto, S.; Kosho, T.; Hatamochi, A.; Honda, T.; Yamaguchi, T.; Okamoto, N.; Miyake, N.; Yamada, S.; Sugahara, K. Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency. Clin. Biochem. 2017, 50, 670–677. [Google Scholar] [CrossRef] [Green Version]
  143. Malfait, F.; Syx, D.; Vlummens, P.; Symoens, S.; Nampoothiri, S.; Hermanns-Lê, T.; Van Laer, L.; De Paepe, A. Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum. Mutat. 2010, 31, 1233–1239. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Malfait, F.; Francomano, C.; Byers, P.; Belmont, J.; Berglund, B.; Black, J.; Bloom, L.; Bowen, J.M.; Brady, A.F.; Burrows, N.P.; et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am. J. Med. Genet. C Semin. Med. Genet. 2017, 175, 8–26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Malfait, F.; Castori, M.; Francomano, C.A.; Giunta, C.; Kosho, T.; Byers, P.H. The Ehlers-Danlos syndromes. Nat. Rev. Dis. Primers 2020, 6, 64. [Google Scholar] [CrossRef] [PubMed]
  146. Shimizu, K.; Okamoto, N.; Miyake, N.; Taira, K.; Sato, Y.; Matsuda, K.; Akimaru, N.; Ohashi, H.; Wakui, K.; Fukushima, Y.; et al. Delineation of dermatan 4-O-sulfotransferase 1 deficient Ehlers-Danlos syndrome: Observation of two additional patients and comprehensive review of 20 reported patients. Am. J. Med. Genet. A 2011, 155A, 1949–1958. [Google Scholar] [CrossRef]
  147. Voermans, N.C.; Kempers, M.; Lammens, M.; van Alfen, N.; Janssen, M.C.; Bönnemann, C.; van Engelen, B.G.; Hamel, B.C. Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation. Am. J. Med. Genet. A 2012, 158A, 850–855. [Google Scholar] [CrossRef] [Green Version]
  148. Mendoza-Londono, R.; Chitayat, D.; Kahr, W.H.; Hinek, A.; Blaser, S.; Dupuis, L.; Goh, E.; Badilla-Porras, R.; Howard, A.; Mittaz, L.; et al. Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am. J. Med. Genet. A 2012, 158A, 1344–1354. [Google Scholar] [CrossRef]
  149. Winters, K.A.; Jiang, Z.; Xu, W.; Li, S.; Ammous, Z.; Jayakar, P.; Wierenga, K.J. Re-assigned diagnosis of D4ST1-deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) after initial diagnosis of Marden-Walker syndrome. Am. J. Med. Genet. A 2012, 158A, 2935–2940. [Google Scholar] [CrossRef]
  150. Janecke, A.R.; Li, B.; Boehm, M.; Krabichler, B.; Rohrbach, M.; Müller, T.; Fuchs, I.; Golas, G.; Katagiri, Y.; Ziegler, S.G.; et al. The phenotype of the musculocontractural type of Ehlers-Danlos syndrome due to CHST14 mutations. Am. J. Med. Genet. A 2016, 170A, 103–115. [Google Scholar] [CrossRef] [Green Version]
  151. Alazami, A.M.; Al-Qattan, S.M.; Faqeih, E.; Alhashem, A.; Alshammari, M.; Alzahrani, F.; Al-Dosari, M.S.; Patel, N.; Alsagheir, A.; Binabbas, B.; et al. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue. Hum. Genet. 2016, 135, 525–540. [Google Scholar] [CrossRef]
  152. Sandal, S.; Kaur, A.; Panigrahi, I. Novel mutation in the CHST14 gene causing musculocontractural type of Ehlers-Danlos syndrome. BMJ Case Rep. 2018, 2018, bcr2018226165. [Google Scholar] [CrossRef]
  153. Uehara, M.; Kosho, T.; Yamamoto, N.; Takahashi, H.E.; Shimakura, T.; Nakayama, J.; Kato, H.; Takahashi, J. Spinal manifestations in 12 patients with musculocontractural Ehlers-Danlos syndrome caused by CHST14/D4ST1 deficiency (mcEDS-CHST14). Am. J. Med. Genet. A 2018, 176, 2331–2341. [Google Scholar] [CrossRef]
  154. Uehara, M.; Oba, H.; Hatakenaka, T.; Ikegami, S.; Kuraishi, S.; Takizawa, T.; Munakata, R.; Mimura, T.; Yamaguchi, T.; Kosho, T.; et al. Posterior spinal fusion for severe spinal deformities in musculocontractural Ehlers-Danlos syndrome: Detailed observation of a novel case and review of 2 reported cases. World Neurosurg. 2020, 143, 454–461. [Google Scholar] [CrossRef]
  155. Minatogawa, M.; Unzaki, A.; Morisaki, H.; Syx, D.; Sonoda, T.; Janecke, A.R.; Slavotinek, A.; Voermans, N.C.; Lacassie, Y.; Mendoza-Londono, R.; et al. Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14). J. Med. Genet. 2022, 59, 865–877. [Google Scholar] [CrossRef]
  156. Zhou, Y.Y.; Du, Y.F.; Lu, Q.; Zhai, X.Z.; Shi, M.F.; Chen, D.Y.; Liu, S.R.; Zhong, Y. Case Report: A novel mutation identified in CHST14 gene in a fetus with structural abnormalities. Front. Genet. 2022, 13, 853907. [Google Scholar] [CrossRef]
  157. Qian, H.; Zhou, T.; Zheng, N.; Lu, Q.; Han, Y. Case report: Multiple gastrointestinal perforations in a rare musculocontractural Ehlers-Danlos syndrome with multiple organ dysfunction. Front. Genet. 2022, 13, 846529. [Google Scholar] [CrossRef]
  158. Kosho, T.; Mizumoto, S.; Watanabe, T.; Yoshizawa, T.; Miyake, N.; Yamada, S. Recent advances in the pathophysiology of musculocontractural Ehlers-Danlos syndrome. Genes 2019, 11, 43. [Google Scholar] [CrossRef] [Green Version]
  159. Miyake, N.; Kosho, T.; Matsumoto, N. Ehlers Danlos syndrome with glycosaminoglycan abnormalities. Adv. Exp. Med. Biol. 2021, 1348, 235–249. [Google Scholar]
Genes 14 00509 g001 550
Figure 1. Common GAG-linker region and repeating disaccharide region of DS and CS with their potential sulfation sites. The DS backbone is composed of IdoUA and GalNAc, whereas CS is a stereoisomer of DS that includes GlcUA instead of IdoUA. These carbohydrate residues may be sulfated at various positions indicated by “SO3−”. It should be noted that sulfation modification of the hydroxy group occurs with various combinations but not all the hydroxy groups. 4-O-Sulfation on GalNAc residues in both DS and CS predominantly occurs in mammals. The linkage region tetrasaccharide, IdoUA-Gal-Gal-Xyl-, was isolated from DS-PGs of bovine aorta [25].
Figure 1. Common GAG-linker region and repeating disaccharide region of DS and CS with their potential sulfation sites. The DS backbone is composed of IdoUA and GalNAc, whereas CS is a stereoisomer of DS that includes GlcUA instead of IdoUA. These carbohydrate residues may be sulfated at various positions indicated by “SO3−”. It should be noted that sulfation modification of the hydroxy group occurs with various combinations but not all the hydroxy groups. 4-O-Sulfation on GalNAc residues in both DS and CS predominantly occurs in mammals. The linkage region tetrasaccharide, IdoUA-Gal-Gal-Xyl-, was isolated from DS-PGs of bovine aorta [25].
Genes 14 00509 g001
Genes 14 00509 g002 550
Figure 2. Biosynthetic pathway of DS side chain of PGs by diverse glycosyltransferases, epimerases, and sulfotransferases. Following the biosynthesis of core proteins (green), the common GAG-protein linker region, GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1-, is constructed by XylT, GalT-I, GalT-II, and GlcAT-I on the specific Ser residue(s) of core proteins. After the formation of the linker region, chondroitin synthases build up the chondroitin backbone. Subsequently, the epimerization of GlcUA moieties as well as sulfation of mainly GalNAc and a small proportion of IdoUA residues are catalyzed by DSE as well as D4ST and UST, respectively. Each enzyme and its coding gene are indicated by blue and red characters, respectively.
Figure 2. Biosynthetic pathway of DS side chain of PGs by diverse glycosyltransferases, epimerases, and sulfotransferases. Following the biosynthesis of core proteins (green), the common GAG-protein linker region, GlcUAβ1-3Galβ1-3Galβ1-4Xylβ1-, is constructed by XylT, GalT-I, GalT-II, and GlcAT-I on the specific Ser residue(s) of core proteins. After the formation of the linker region, chondroitin synthases build up the chondroitin backbone. Subsequently, the epimerization of GlcUA moieties as well as sulfation of mainly GalNAc and a small proportion of IdoUA residues are catalyzed by DSE as well as D4ST and UST, respectively. Each enzyme and its coding gene are indicated by blue and red characters, respectively.
Genes 14 00509 g002
Table
Table 1. Representations of core proteins of human DS-PGs.
Table 1. Representations of core proteins of human DS-PGs.
DS-PGsCoding GenesChromosomal MappingGene ID aMIM No. bGAG Type
(Number)		Human Genetic Disorders
DecorinDCN12q21.331634125255
610048		DS/CS (1)Congenital stromal corneal dystrophy
BiglycanBGNXq28633300106
300989
301870		DS/CS (2)Spondyloepimetaphyseal dysplasia, X-linked
Meester–Loeys syndrome
EpiphycanEPYC12q21.331833601657DS/CS (2–3)—
EndocanESM15q11.211082601521DS/CS (1)—
a, National Center for Biotechnology Information (NCBI); b, Mendelian Inheritance in Man.
Table
Table 2. General properties of human DSE, DSEL, and CHST14.
Table 2. General properties of human DSE, DSEL, and CHST14.
EnzymeCoding GeneChromosomal MappingGene IDMIM No.Human Genetic Disorders
DSEDSE6q22.129940605942
615539		Ehlers-Danlos syndrome musculocontractural type 2
DSELDSEL18q22.192126611125Bipolar disorder
D4STCHST1415q15.1113189601776
608429		Ehlers-Danlos syndrome musculocontractural type 1; adducted thumb–clubfoot syndrome
USTUST6q25.110090610752Multiple congenital anomalies of the heart and central nervous system
Table
Table 3. Pathogenic variants of DSE, DSEL, and CHST14.
Table 3. Pathogenic variants of DSE, DSEL, and CHST14.
Coding GeneHuman Genetic DisordersVariants
DSEEhlers-Danlos syndrome musculocontractural type 2p.Ser268Leu, p.Arg267Gly, p.Tyr320*, p.Val333Cysfs*4, p.Pro384Trpfs*9, p.Tyr867*, and p.Val938Asp
DSELBipolar disorderp.Val287Ile, p.Pro673Ser, p.Tyr730Cys, p.Pro942Ser, and p.Ile1113Met
Diaphragmatic defectp.Met14Ile, p.Asn276Ser, p.Pro683Ser, p.Tyr740Cys, p.Thr842Ser, and p.Asp991Asn
CHST14Ehlers-Danlos syndrome musculocontractural type 1; adducted thumb–clubfoot syndromep.Arg29Glyfs*113, p.Val49*, p.Lys69*, p.Gln133Argfs*14, p.Arg135Gly, p.Leu137Gln, p.Phe209Ser, p.Arg213Pro, p.Arg218Ser, p.Lys226Alafs*16, p.Arg274Pro, p.Met280Leu, p.Pro281Leu, p.Cys289Ser, p.Tyr293Cys, and p.Glu334Glyfs*107
USTMultiple congenital anomalies of the heart and central nervous system0.63 Mb deletion in 6q25.1, which includes TAB2, LATS1, and UST
Asterisks indicate the termination codon. The “fs*number” represents a frame shifting change with the new reading flame being open for amino acids and termination codon.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Mizumoto, S.; Yamada, S. Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome. Genes 2023, 14, 509. https://doi.org/10.3390/genes14020509

AMA Style

Mizumoto S, Yamada S. Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome. Genes. 2023; 14(2):509. https://doi.org/10.3390/genes14020509

Chicago/Turabian Style

Mizumoto, Shuji, and Shuhei Yamada. 2023. "Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome" Genes 14, no. 2: 509. https://doi.org/10.3390/genes14020509

APA Style

Mizumoto, S., & Yamada, S. (2023). Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome. Genes, 14(2), 509. https://doi.org/10.3390/genes14020509

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop