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Étude des conséquences de la déficience génétique en ß1,3-galactosyltransférase 6 (ß3GalT6) sur la pathogénie d’une maladie génétique rare, le syndrome d’Ehlers-Danlos (SED)

Abstract : Proteoglycans (PGs) play important roles in many physiological processes, including cell proliferation, differentiation and migration. PGs are composed of linear heteropolysaccharide chains, called glycosaminoglycans (GAGs), which are covalently attached to a core protein through a tetrasaccharide linkage. The addition of the third residue (galactose) of the linkage is catalyzed by ß1,3-galactosyltransferase 6 (ß3GalT6), a key glycosyltransferase in GAG initiation. Recently, mutations of ß3GalT6 have been associated to Ehlers-Danlos Syndrome (EDS), a group of rare and severe genetic connective tissue disorders. However, the role of ß3GalT6 defects in EDS pathogeny remains unknown. In my thesis, we showed that ß3GalT6 defective dermal fibroblasts of affected patients exhibited a marked reduction in GAG anabolism associated to a significant delay in wound closure compared to control cells. The ß3GalT6 gain- and loss-of-function studies demonstrated that B3GALT6 gene deletion in control fibroblasts affects the synthesis of GAGs chains. Interestingly, GAG anabolism and cell migration were restored when ß3GalT6 is overexpressed in patient fibroblasts, which could be the starting point to the development of therapeutic strategies against the loss of GAG synthesis and defect of cell migration observed in EDS. This work provides a better understanding of the crucial role of ß3GalT6 in EDS pathogeny
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Xiaomeng Pang. Étude des conséquences de la déficience génétique en ß1,3-galactosyltransférase 6 (ß3GalT6) sur la pathogénie d’une maladie génétique rare, le syndrome d’Ehlers-Danlos (SED). Médecine humaine et pathologie. Université de Lorraine, 2016. Français. ⟨NNT : 2016LORR0190⟩. ⟨tel-01665817⟩

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