Molecular characterization of beta1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS).

Date publication

septembre 2010

Auteurs

Membres identifiés du Cancéropôle Est :
Dr FOURNEL-GIGLEUX Sylvie , Dr OUZZINE Mohamed

Tous les auteurs :
Bui C, Talhaoui I, Chabel M, Mulliert G, Coughtrie MW, Ouzzine M, Fournel-Gigleux S

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/20691685

Résumé

beta1,4-Galactosyltransferase 7 (beta4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta4GalT7 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 beta4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta4GalT7 defects associated with altered GAG synthesis in EDS.

Référence

FEBS Lett. 2010 Sep 24;584(18):3962-8