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|Title:||Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (β4GalT-7) deficient form of Ehlers-Danlos syndrome|
Van kuppevelt, T.H.
|Citation:||Götte, M., Spillmann, D., Yip, G.W., Versteeg, E., Echtermeyer, F.G., Van kuppevelt, T.H., Kiesel, L. (2008-04-01). Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (β4GalT-7) deficient form of Ehlers-Danlos syndrome. Human Molecular Genetics 17 (7) : 996-1009. ScholarBank@NUS Repository. https://doi.org/10.1093/hmg/ddm372|
|Abstract:||Reduced activity of β4-galactosyltransferase 7 (β4GalT-7), an enzyme involved in synthesizing the glycosaminoglycan linkage region of proteoglycans, is associated with the progeroid form of Ehlers-Danlos syndrome (EDS). In the invertebrates Drosophila melanogaster and Caenorhabditis elegans, mutations in β4GalT-7 affect biosynthesis of heparan sulfate (HS), a modulator of several biological processes relevant to wound repair. We have analyzed structural alterations of HS and their functional consequences in human β4GalT-7Arg270Cys mutant EDS and control fibroblasts. HS disaccharide analysis by reversed phase ion-pairing chromatography revealed a reduced sulfation degree of HS paralleled by altered immunostaining patterns for the phage-display anti-HS antibodies HS4E4 and RB4EA12 in β4GalT-7 mutant fibroblasts. Real-time PCR-analysis of 44 genes involved in glycosaminoglycan biosynthesis indicated that the structural alterations in HS were not caused by differential regulation at the transcriptional level. Scratch wound closure was delayed inβ4GalT-7-deficient cells, which could be mimicked by enzymatic removal of HS in control cells. siRNA-mediated knockdown of β4GalT-7 expression induced morphological changes in control fibroblasts which suggested altered cell-matrix interactions. Adhesion of β4GalT-7 deficient cells to fibronectin was increased while actin stress fiber formation was impaired relative to control cells. Also collagen gel contraction was delayed in the β4GalT-7 mutants which showed a reduced formation of pseudopodia and filopodia, less efficient penetration of the collagen gels and a diminished formation of collagen suprastructures. Our study suggests an HS-dependent basic mechanism behind the altered wound repair phenotype of β4GalT-7-deficient EDS patients. © The Author 2007. Published by Oxford University Press. All rights reserved.|
|Source Title:||Human Molecular Genetics|
|Appears in Collections:||Staff Publications|
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