Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers-Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis
Open accessAbstract
Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity.
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In this patient, no pronounced ultrastructural abnormalities of dermal collagen fibrils were noted, but immunofluorescent stainings of collagen types I, III, and V and fibronectin showed evidence of abnormal ECM assembly.
“In this patient, no pronounced ultrastructural abnormalities of dermal collagen fibrils were noted, but immunofluorescent stainings of collagen types I, III, and V and fibronectin showed evidence of abnormal ECM assembly”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Syx et al. [2015] analyzed fibroblasts from a patient harboring p.(Arg267Gly) and showed a minor fraction of decorin DS was present, consisting of IdoA-containing disaccharides, attributable to residual DSE activity or compensating DSE2 activity.
“Syx et al. [2015] analyzed fibroblasts from a patient harboring the p.(Arg267-Gly) substitution and could show that a minor fraction of decorin DS was present, consisting of IdoA-containing disaccharides, which could be attributed to residual DSE activity, or compensating DSE2 activity.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Deterioration in vision of the right eye because of a lacquer crack in Bruch's membrane adjacent to the right fovea was described in a 15-year-old male.
“Progressive visual field loss was described in a 31-year-old female [Kosho et al., 2010], deterioration in vision of the right eye because of the lacquer crack in Bruch's membrane adjacent to right fovea in a 15-year-old male [Syx et al., 2015], and right-sided blindness because of retinal detachment in a 45-year-old female [Janecke et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
GAG chains of decorin from affected skin fibroblasts contained exclusively CS and no DS disaccharides, while controls contained mainly DS disaccharides (approximately 95%).
“GAG chains of decorin from the affected skin fibroblasts contained exclusively CS and no DS disaccharides, while those from the controls contained mainly DS disaccharides (approximately 95%)”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Disaccharide composition analysis of CS/DS chains from affected skin fibroblasts showed negligible DS and excess CS, suggested to result from impaired 4-O-sulfation lock due to D4ST1 deficiency followed by backepimerization from IdoA to GlcA.
“Disaccharide composition analysis of CS/DS chains isolated from the affected skin fibroblasts in these two patients showed a negligible amount of DS and excess amount of CS, which was suggested to result from impaired 4-O-sulfation lock due to D4ST1 deficiency, followed by backepimerization from IdoA to GlcA”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Two deliveries were described in a female patient with EDS caused by DSE deficiency, followed by uterine and bladder prolapse.
“Two deliveries were described in a female patient with EDS caused by DSE deficiency, followed by uterine and bladder prolapse”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Two homozygous missense DSE mutations, p.(Arg267Gly) and p.(Ser268Leu), have been detected in DSE-deficient EDS.
“Two homozygous missense mutations (p.(Arg267Gly); p.( Ser268Leu)) have been detected”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Some DS moieties were present in the decorin GAG in fibroblasts derived from patients with EDS caused by DSE deficiency, whereas DS was completely replaced by CS in fibroblasts derived from patients with EDS caused by CHST14/D4ST1 deficiency.
“presumably associated with the glycobiological finding that some DS moieties were present in the decorin GAG in the fibroblasts derived from patients with EDS caused by DSE deficiency, whereas DS was completely replaced by CS in the fibroblasts derived from patients with EDS caused by CHST14/D4ST1 deficiency [Syx et al., 2015].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Phenotypic features in three patients with EDS caused by DSE deficiency seemed to be milder than those in patients with EDS caused by D4ST1 deficiency.
“Phenotypic features in three patients with EDS caused by DSE deficiency seemed to be milder than those in patients with EDS caused by D4ST1 deficiency, presumably associated with the glycobiological finding that some DS moieties were present in the decorin GAG in the fibroblasts derived from patients with EDS caused by DSE deficiency, whereas DS was completely replaced by CS in the fibroblasts”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
Another patient had a pelviureteric junction obstruction requiring nephrostomy in the neonatal period.
“Another patient had a pelviureteric junction obstruction requiring nephrostomy in the neonatal period [Syx et al., 2015].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Syx et al., 2015
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References 38 · Cited by 84
- Authors
- 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., De Paepe, A., & Malfait, F.
- Affiliations
- Ghent University Hospital (BE)
- Center for Medical Genetics; Ghent University Hospital; Ghent Belgium
- University Medical Center Utrecht (NL)
- Department of Clinical Genetics; Erasmus Medical Center; Rotterdam The Netherlands
- Birmingham Women's Hospital (GB)
- Nottingham City Hospital (GB)
- Area de Genetica Clinica y Molecular, Hospital Vall d ‘Hebron; Barcelona Spain
- University Hospital Heidelberg (DE)
- Department of Dermatopathology; Liège University Hospital; Liège Belgium
- Corresponding author
- Malfait, Fransiska
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2015-04-06
- Volume
- 36
- Issue
- 5
- Pages
- 535-547
- ISSN
- 1059-7794 (ISSN-L)
- OpenAlex
- W2030528955
- Cited by
- 84
- References
- 38
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 10 · 2021: 11 · 2020: 13 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 3 · 2015: 4 · 2014: 1 · 2012: 1
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Open Repository and Bibliography (University of Liège) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek (G.0171.05)
- Universiteit Gent (08/01M01108)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- locus heterogeneity, connective tissue fragility, decorin, chondroitin sulfate, glycosaminoglycan synthesis, congenital contractures, craniofacial anomalies, genotype-phenotype correlation, fibroblasts
- MeSH terms
- Adolescent, Adult, Amino Acid Sequence, Antigens, Neoplasm, Biopsy, Child, Collagen, Dermatan Sulfate, DNA-Binding Proteins, Ehlers-Danlos Syndrome, Exons, Extracellular Matrix, Female, Fibronectins, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Proteins, Pedigree, Phenotype, RNA, Messenger, Skin, Sulfotransferases, Sequence Alignment, Genetic Heterogeneity, Facies, Young Adult
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