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

Autor: Ingrid Hausser, Jenny Morton, Merel C. Maiburg, Ingrid M.B.H. van de Laar, Delfien Syx, Tim Van Damme, Sofie Symoens, Anne De Paepe, Miguel del Campo, Trinh Hermanns-Lê, Fransiska Malfait, Mohnish Suri
Přispěvatelé: Clinical Genetics
Rok vydání: 2015
Předmět:
Male
Decorin
Biopsy
Iduronic acid
DSE
Case Reports
Review
EDS
chemistry.chemical_compound
Genetics(clinical)
Non-U.S. Gov't
Child
Genetics (clinical)
Skin
Medicine(all)
Dermatan sulfate epimerase-1
Research Support
Non-U.S. Gov't
Exons
Extracellular Matrix
Neoplasm Proteins
Pedigree
DNA-Binding Proteins
medicine.anatomical_structure
Phenotype
Biochemistry
Female
Collagen
CHST14
Sulfotransferases
Adult
medicine.medical_specialty
Adolescent
Molecular Sequence Data
Connective tissue
Dermatan Sulfate
Biology
Research Support
Dermatan sulfate
Genetic Heterogeneity
Young Adult
Antigens
Neoplasm
Internal medicine
medicine
Genetics
Journal Article
Humans
Chondroitin sulfate
Amino Acid Sequence
RNA
Messenger
Genetic heterogeneity
Facies
medicine.disease
Dermatan 4-O-sulfotransferase-1
Fibronectins
carbohydrates (lipids)
Endocrinology
chemistry
Proteoglycan
Ehlers–Danlos syndrome
Mutation
biology.protein
Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome
Sequence Alignment
Zdroj: Human Mutation, 36(5), 535-547. Wiley-Liss Inc.
Human Mutation, 36(5), 535. Wiley-Liss Inc.
ISSN: 1059-7794
Popis: 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.
Databáze: OpenAIRE
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