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, les conséquences fonctionnelles et structurales des mutations de la ?3GalT6 et leur rôle dans la pathogénie du SEDsp, (i) en réalisant une caractérisation moléculaire et fonctionnelle de la protéine recombinante humaine et (ii) en développant un modèle cellulaire déficient en ?3GalT6 pour étudier l'impact des défauts génétiques sur les fonctions métaboliques des cellules

, Pour ce faire, nous avons produit dans la bactérie et purifié différentes formes tronquées solubles de la ?3GalT6 fusionnées avec la Maltose Binding Protein (MBP). Les essais enzymatiques ont permis de déterminer les constantes cinétiques KM et kcat de la protéine sauvage. Les mutants de la ?3GalT6 seront étudiés ultérieurement selon la même approche

, La seconde partie de ce travail de thèse a été de réaliser un modèle cellulaire déficient en ?3GalT6 en utilisant la technologie CRISPR/Cas9. Les clones déficients obtenus présentent (i) un très faible niveau d'expression de l'ARNm, (ii) une absence d'activité galactosyltransférase et (iii) un défaut de synthèse des GAGs endogènes ou à partir d'un substrat exogène xylosidique. Nous avons initié l'analyse de la capacité de la ?3GalT6 sauvage et de deux mutants

, nous avons acquis une meilleure compréhension de l'implication de la ?3GalT6 dans la pathogénie du SEDsp et mieux compris le lien entre la perte de fonction de la ?3GalT6 et les conséquences métaboliques et cellulaires de cette déficience génétique. Ces résultats, mis en lien avec la sévérité des symptômes cliniques observés chez les patients

, Mot clés : Syndrome d'Ehlers-Danlos

. Proteoglycans, PGs are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein through a tetrasaccharide linkage ?Glucuronic acid-?1,3-Galactose-?1,3-Galactose-?1,4-Xylose-?1-O-?. The addition of the third residue (galactose) is catalyzed by the ?1,3-Galactosyltransferase 6 (?3GalT6), a key glycosyltransferase in GAG initiation. Our group and others discovered that mutations of ?3GalT6 are associated to a spondylodysplastic form of Ehlers-Danlos Syndrome (spEDS), a severe connective tissue disorder characterized by skin and bone fragility, musculoskeletal malformations, delayed wound healing, joint hyperlaxity and intellectual disabilities. The objectives of this project is to understand the functional and structural consequences of ?3GalT6 mutations in the development of spEDS, (i) achieving the molecular and functional characterization of the recombinant human ?3GalT6 and (ii) to develop cellular models

, The first part of the project is dedicated to the determination of mutation impact on the ?3GalT6 function. For this, we produce and purify several truncated soluble forms of h?3GalT6 in fusion to Maltose Binding Protein. The enzymatic activity tests have determined a KM of 30 µM and a kcat of 0,05 min -1 on wild-type enzyme

, Deficient clones obtained present (i) a low level of RNA expression, (ii) an absence of galactosyltransferase activity and (iii) a defect on endogenous GAG synthesis or with exogenous substrate. We also analyze the capacity for WT ?3GalT6 and two mutants (Asp207His and Gly217Ser) to restore GAGs synthesis in deficient cells. From this work, we better understand the implication of ?3GalT6 in the pathology of spEDS and relationships between ?3GalT6 loss of function, cellular consequences of genetic defect. Those results linked with the severity of spEDS clinical symptoms observed in patients, would help clinicians with management and clinical monitoring of spEDS patients, The second part of the project is achieving to develop a ?3GalT6 deficient cell model using the CRISPR/Cas 9 technology, pp.3-6