Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers-Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis

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.

Melanoma Cell Adhesion and Migration Is Modulated by the Uronyl 2-O Sulfotransferase

“…Recently, a patient with a microdeletion on chromosome 6q25.1 was described with among other symptoms an Ehlers-Danlos syndrome in skin [45]. The microdeletion included the lack of human UST gene indicating that the minor sulfation of CS/DS affects also the organization of the extracellular matrix, similar to the DS [46]. Understanding the impact of Ust and 2-O sulfation might identify potential therapeutic targets in melanoma metastasis.…”

Modeling Human Craniofacial Disorders in Xenopus

“…They are mainly characterized by skin hyperextensibility, articular hypermobility and tissue fragility. The condition also has a distinctive craniofacial component including micrognathia, high and/or cleft palate, brachycephaly, hypertelorism, downslanting palpebral fissures and low-set ears [98], [99]. It is caused by autosomal recessive loss-of-function mutations in genes encoding dermatan sulfate (DS) biosynthetic enzymes: dermatan 4-O-sulfotransferase 1 ( CHST14 ) or DS epimerase-1 ( DSE ).…”

Pathophysiological Significance of Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders

“…Syx et al reported another family with a homozygous DSE missense variant (p.Arg267Gly) [43]. The clinical manifestations of the two affected adult sisters showed craniofacial dysmorphic features, congenital clubfeet, long and slender fingers with contracture, muscle weakness, smooth, hyperextensible, and translucent skin, and the formation of large hematomas.…”

“…The clinical manifestations of the two affected adult sisters showed craniofacial dysmorphic features, congenital clubfeet, long and slender fingers with contracture, muscle weakness, smooth, hyperextensible, and translucent skin, and the formation of large hematomas. No obvious alteration in the architecture of collagen fibrils was detected in DSE-deficient patients [43]. In contrast, CHST14-deficient patients show collagen bundles with collagen fibrils of various diameters, the intermittent presence of small flower-like fibrils, and irregular spaces filled with granulofilamentous deposits [43].…”

“…No obvious alteration in the architecture of collagen fibrils was detected in DSE-deficient patients [43]. In contrast, CHST14-deficient patients show collagen bundles with collagen fibrils of various diameters, the intermittent presence of small flower-like fibrils, and irregular spaces filled with granulofilamentous deposits [43]. Thus, DSE-deficient patients may have a milder form of the EDS musculocontractural type than CHST14-deficient patients.…”