Genetics and biochemistry of some human blood groups

Abstract

The antigenic structures associated with the functional alleles of the human ABO, H, Lewis and P blood group genetic systems are carbohydrate and hence are secondary products of the blood group genes. The carbohydrate structures that confer A, B, H and Lewis specificities are part of glycosphingolipid molecules on cell surfaces and of glycoprotein molecules in secretions. The carbohydrate chains of the glycolipids or glycoproteins are built up by the sequential action of a series of glycosyltransferase enzymes determined by genes at several different loci. The genes at the ABO, H and Lewis loci are concerned only with the final stages of the biosynthesis of the carbohydrate structures; the functional alleles each control the formation of a single glycosyltransferase. The enzymic product of the H gene is an α-2-L-fucosyltransferase that conveys the sugar L-fucose to terminal β-D-galactosyl residues. The H-active structures thus formed constitute acceptors for the sugar N -acetyl-D-galactosamine, added by the A -gene specified enzyme or D-galactose, added by the B -gene specified enzyme. The regulatory gene Se controls the activity of the H gene in cells synthesizing the secreted glycoproteins and other regulatory genes modify the expression of the A, B and H genes in the cells synthesizing the glycolipids. The functional allele at the Lewis locus, Le , controls the formation of an α-4-L-fucosyltransferase, that conveys L-fucose to subterminal N -acetylglucosamine residues. If the adjacent terminal β-galactosyl residue is unsubstituted the structure formed has Le a specificity; if the β-galactosyl unit is substituted with α-2-linked fucose the structure has Le b specificity. The genetics of the P blood group system are less well understood than those of the ABO and Lewis systems. A glycoprotein isolated from hydatid cyst fluid provided a convenient source of P 1ˉ and P k -active substance for immunochemical studies and allowed the structure of the P 1 determinant to be established. P 1 , P k and P antigens have now been isolated from red cells and found to be glycosphingolipids. The antigen, P k , ceramide trihexoside, is the precursor of the P antigen, globoside, but the precise genetic and biosynthetic relation of the P 1 specific structure to P and P k determinants has still to be clarified.