Molecular genetic basis of the human Forssman glycolipid antigen negativity

Abstract

Forssman heterophilic glycolipid antigen has structural similarity to the histo-blood group A antigen, and the GBGT1 gene encoding the Forssman glycolipid synthetase (FS) is evolutionarily related to the ABO gene. The antigen is present in various species, but not in others including humans. We have elucidated the molecular genetic basis of the Forssman antigen negativity in humans. In the human GBGT1 gene, we identified two common inactivating missense mutations (c.688G>A [p.Gly230Ser] and c.887A>G [p.Gln296Arg]). The reversion of the two mutations fully restored the glycosyltransferase activity to synthesize the Forssman antigen in vitro. These glycine and glutamine residues are conserved among functional GBGT1 genes in Forssman-positive species. Furthermore, the glycine and serine residues represent those at the corresponding position of the human blood group A and B transferases with GalNAc and galactose specificity, respectively, implicating the crucial role the glycine residue may play in the FS α1,3-GalNAc transferase activity.

FORS, a new histo-blood group: A current review

“…Nowadays, it is known that the FORS is expressed on RBCs and it has been found in guinea pigs, horses, hamsters, sheep and chickens but could be also found in other body fluids, in cells, several human tissues and organs and is heritable [1,2,4,7].…”

“…The Forssman Ag is a glycolipid with the structure GalNAcα(1,3) GalNAcβ(1,3)Galα(1,4)Galβ(1,4)Glc, as shown in Figure 1 [4,13]. DNA sequence analysis of GBGT1 showed changes arginine at position 296 to glutamine.…”

“…The Forssman Ag was first discovered in 1911 by John Frederick Forssman after injecting rabbits with a suspension of kidney tissue from guinea pig and the rabbits were able to produce Ab that haemolysed sheep RBCs [4].…”

“…Forssman Ag, synthesized by Fs-synthase, a homologous enzyme of the AB0 transferase (globoside 3-α-N-acetyl-Dgalactosaminyltransferase), terminates with α3-N-acetylgalactosamine, in analogy with blood group A Ag [1,3,4,6,7].…”

“…but not in others (rabbits, pigs, humans, etc. ), referred to as FORS positive species and FORS negative species, respectively [4,7,8].…”