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Genetic heterogeneity and clinical variability in musculocontractural Ehlers–Danlos syndrome caused by impaired dermatan sulfate biosynthesis

(2015) HUMAN MUTATION. 36(5). p.535-547
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Abstract
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.
Keywords
ADDUCTED THUMB, THUMB-CLUBFOOT SYNDROME, CHONDROITIN/DERMATAN SULFATE, FOOT SYNDROME, IDURONIC ACID, CHST14 GENE, DERMATAN-4-SULFOTRANSFERASE, MUTATIONS, CONTRACTURES, PROTEIN, dermatan sulfate epimerase-1, DSE, Ehlers–Danlos syndrome, CHST14, dermatan 4-O-sulfotransferase-1, EDS

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Citation

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Chicago
Syx, Delfien, Tim Van Damme, Sofie Symoens, Merel C Maiburg, Ingrid van de Laar, Jenny Morton, Mohnish Suri, et al. 2015. “Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers–Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis.” Human Mutation 36 (5): 535–547.
APA
Syx, D., Van Damme, T., Symoens, S., Maiburg, M. C., van de Laar, I., Morton, J., Suri, M., et al. (2015). Genetic heterogeneity and clinical variability in musculocontractural Ehlers–Danlos syndrome caused by impaired dermatan sulfate biosynthesis. HUMAN MUTATION, 36(5), 535–547.
Vancouver
1.
Syx D, Van Damme T, Symoens S, Maiburg MC, van de Laar I, Morton J, et al. Genetic heterogeneity and clinical variability in musculocontractural Ehlers–Danlos syndrome caused by impaired dermatan sulfate biosynthesis. HUMAN MUTATION. 2015;36(5):535–47.
MLA
Syx, Delfien, Tim Van Damme, Sofie Symoens, et al. “Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers–Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis.” HUMAN MUTATION 36.5 (2015): 535–547. Print.
@article{6933150,
  abstract     = {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.},
  author       = {Syx, Delfien and Van Damme, Tim and Symoens, Sofie and Maiburg, Merel C and van de Laar, Ingrid and Morton, Jenny and Suri, Mohnish and Del Campo, Miguel and Hausser, Ingrid and Hermanns-L{\^e}, Trinh and De Paepe, Anne and Malfait, Fransiska},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  language     = {eng},
  number       = {5},
  pages        = {535--547},
  title        = {Genetic heterogeneity and clinical variability in musculocontractural Ehlers--Danlos syndrome caused by impaired dermatan sulfate biosynthesis},
  url          = {http://dx.doi.org/10.1002/humu.22774},
  volume       = {36},
  year         = {2015},
}

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