Title |
Defective glycosylation of decorin and biglycan, altered collagen structure, and abnormal phenotype of the skin fibroblasts of an Ehlers–Danlos syndrome patient carrying the novel Arg270Cys substitution in galactosyltransferase I (β4GalT-7)
|
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Published in |
Journal of Molecular Medicine, April 2006
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DOI | 10.1007/s00109-006-0046-4 |
Pubmed ID | |
Authors |
Daniela G. Seidler, Muhammad Faiyaz-Ul-Haque, Uwe Hansen, George W. Yip, Syed H. E. Zaidi, Ahmad S. Teebi, Ludwig Kiesel, Martin Götte |
Abstract |
The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders affecting skin and joint function. Molecular defects in extracellular matrix proteins, including collagen (type I, III, and V) and tenascin X are associated with different forms of EDS. Compound heterozygous mutations in the B4GALT7 gene, resulting in aberrant glycosylation of the dermatan sulfate proteoglycan decorin, had been described in a single patient affected with the progeroid form of EDS. We have studied the molecular phenotype of decorin, biglycan, and collagen type I containing fibrils in skin fibroblasts of a patient carrying the novel homozygous C808T point mutation in the B4GALT7 gene, which causes an Arg270Cys substitution in beta4GalT-7. Compared to control fibroblasts, galactosyltransferase activity in beta4GalT-7(Arg270Cys) cells was approximately three times reduced over a temperature range of 25-41 degrees C. Pulse-chase experiments and confocal microscopy demonstrated that synthesis and secretion of decorin were normal in beta4GalT-7(Arg270Cys) cells. However, about 50% of decorin were synthesized as a protein core in addition to its proteoglycan form. Biglycan was found in a monoglycanated form in addition to its mature form. Glycosaminoglycan chains were of the dermatan/chondroitin sulfate type both in beta4GalT-7(Arg270Cys) and control cells, and epimerization was reduced for decorin and biglycan. Compared to control cells, beta4GalT-7(Arg270Cys) cells showed altered, highly spread or stretched phenotypes and decreased proliferation rates. At the ultrastructural level, an intracellular accumulation of multiple secondary lysosomes and degenerative vacuoles was seen in beta4GalT-7(Arg270Cys) cells. Furthermore, the collagen suprastructures were altered in the beta4GalT-7(Arg270Cys) cells. The reduced beta4GalT-7 activity resulting in defective glycosylation of decorin and biglycan may be responsible for the complex molecular pathology in beta4GalT-7 deficient EDS patients, given the role of these proteoglycans in bone formation, collagen fibrillogenesis, and skeletal muscle development. |
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France | 1 | 2% |
Germany | 1 | 2% |
Unknown | 54 | 90% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 14 | 23% |
Researcher | 13 | 22% |
Professor > Associate Professor | 7 | 12% |
Student > Master | 4 | 7% |
Other | 3 | 5% |
Other | 9 | 15% |
Unknown | 10 | 17% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 12 | 20% |
Medicine and Dentistry | 9 | 15% |
Engineering | 2 | 3% |
Immunology and Microbiology | 2 | 3% |
Other | 8 | 13% |
Unknown | 10 | 17% |