A missense mutation in the FUT6 gene results in total absence of α3-fucosylation of human α1-acid glycoprotein

Abstract

The major α3-fucosyltransferase activity in human plasma is encoded by the gene for fucosyltransferase VI (FUT6). Amissense mutation (Gly-739 → Ala) in this gene is responsible for deficiency of enzyme activity in plasma. To examine whether this fucosyltransferase is the sole enzyme responsible for the α3-fucosylation of serum glycoproteins in the liver, we studied the fucosylation of three glycoproteins in sera of individuals with or without inactivated FUT3 and/or FUT6 gene(s) but with a functional FUT5 gene. α1-Acid glycoprotein was used as the principal reporter protein for liver α3-fucosyltransferase activity, because of its high fucose content. In all individuals with the FUT6 missense mutation Gly-739 → Ala in double dose, no fucosylation of α1-acid glycoprotein was found. This α1-acid glycoprotein was not intrinsically resistant to fucosylation, since it was susceptible to in vitro fucosylation using an α3/4-fucosyltransferase isolated from human milk. The same result was found for α1-antichymotrypsin and α1-protease inhibitor. On the other hand in all individuals with α3-fucosyltransferase activity in plasma, α3-fucosylated glycoforms of the glycoproteins studied were found. The degree of fucosylation of α1-acid glycoprotein was correlated with α3-fucosyltransferase activity (Rs = 0.82). These data indicate that the product of FUT6, but not of FUT3 or of FUT5, is responsible for the α3-fucosylation of glycoproteins produced in liver and suggest that this organ is a major source of α3-fucosyltransferase activity in plasma.