title: Molecular characterization of β1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS).
abstract: β1,4-Galactosyltransferase 7 (β4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized β4GalT7 mutants linked to the progeroid form of Ehlers-Danlos syndrome (EDS), a severe connective tissue disorder. Our results revealed that loss of activity upon L206P substitution due to altered protein folding is the primary cause for the GAG synthesis defect in patients carrying the compound A186D and L206P mutations. We showed that R270C substitution strongly reduced β4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for β4GalT7 defects associated with altered GAG synthesis in EDS.
authors.affiliation: UMR 7561 CNRS-Université de Nancy I, Faculté de Médecine, Vandoeuvre-lès-Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bui
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Talhaoui
authors.forename: Matthieu
authors.initials: M
authors.lastname: Chabel
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mulliert
authors.forename: Michael W H
authors.initials: MW
authors.lastname: Coughtrie
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ouzzine
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel-Gigleux
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004535:Ehlers-Danlos Syndrome / Q000201:enzymology* / Q000235:genetics; D005700:Galactosyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation
chemical_list: D006025:Glycosaminoglycans; D005700:Galactosyltransferases; C063053:xylosylprotein 4-beta-galactosyltransferase