[en] Bi-allelic variants in CHTS-14, encoding dermatan 4-O sulfotransferase-1(D4ST-1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures and developmental abnormalities. 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 of this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondoitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and a second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of a dermal DS protoglycan decorin is impaired in fibroblasts from D4ST1, as well as DS-epi1-deficient patients. However, D4ST1-deficiency, decorin GAG is completely replaced by CS, whereas in DS-epi1-deficency, 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.
Research center :
Center for Medical Genetics, Ghent University Hospital
Disciplines :
Human health sciences: Multidisciplinary, general & others
Author, co-author :
Syx, Delfien; Ghent University Hospital, Belgium > Center of Medical Genetics
Van Damme, Tim; Ghent University Hospital, Belgium > Center of Medical genetics
Symoens, Sofie; Ghent University Hospital, Belgium > Center of Medical Genetics
Maiburg, Merel; University Medical Center Utrecht, The Netherlands > Department of Medical Genetics Utrecht
van de Laar, Ingrid; Erasmus Universiteit Rotterdam - EUR > Department of Clinical Genetics
Morton, Jenny; Birmingham Women's Hospital, United Kingdom > Clinical gentics Unit
Suri, Mohnish; Nottingham City Hospital, United Kingdom > Nottingham Clinical Genetics Service
Del Campo, Miguel; Hospital Vall'Hebron, Barcelona, Spain > Area de Genetica Clinica y Molecular
Hausser, Ingrid; University Clinic Heidelberg, Germany > Institute of Pathology
Hermanns-Lê, Trinh ; Université de Liège > Département des sciences cliniques > Dermatopathologie
De Paepe, Anne; Ghent University Hospital, Belgium > Center of Medical Genetics
Malfait, Fransiska; Ghent University Hospital, Belgium > Center of Medical Genetics
Language :
English
Title :
Genetic heterogeneity and clinical variability in musculocontractural ehlers-danlos syndrome caused by impaired dermatan sulfate biosynthesis
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