Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS)

作者：Bui Catherine; Talhaoui Ibtissam; Chabel Matthieu; Mulliert Guillermo; Coughtrie Michael W H; Ouzzine Mohamed; Fournel Gigleux Sylvie^*

来源：FEBS Letters, 2010, 584(18): 3962-3968.

DOI：10.1016/j.febslet.2010.08.001

• Ehlers-Danlos syndrome
• Point mutation
• Galactosyltransferase defect
• Glycosaminoglycan synthesis
• Congenital glycosyltransferase disorder

beta 1,4-Galactosyltransferase 7 (beta 4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta 4GalT7 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 beta 4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta 4GalT7 defects associated with altered GAG synthesis in EDS.

• 出版日期2010-9-24