Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis
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, t...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
6 April 2015
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| In: |
Human mutation
Year: 2015, Volume: 36, Issue: 5, Pages: 535-547 |
| ISSN: | 1098-1004 |
| DOI: | 10.1002/humu.22774 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1002/humu.22774 Verlag, Volltext: http://onlinelibrary.wiley.com/doi/10.1002/humu.22774/abstract 
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| Author Notes: | Delfien Syx, Tim Van Damme, Sofie Symoens, Merel C. Maiburg, Ingrid van de Laar, Jenny Morton, Mohnish Suri, Miguel Del Campo, Ingrid Hausser, Trinh Hermanns-Lê, Anne De Paepe, and Fransiska Malfait |
| Summary: | 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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| Item Description: | Gesehen am 30.06.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1098-1004 |
| DOI: | 10.1002/humu.22774 |