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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 ?1,3-GalNAc transferase activity.

SUBMITTER: Yamamoto M

PROVIDER: S-EPMC3521167 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Molecular genetic basis of the human Forssman glycolipid antigen negativity.

Yamamoto Miyako M Cid Emili E Yamamoto Fumiichiro F

Scientific reports 20121213

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.88 ...[more]

PMID: 23240079

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Project description:The heterogenetic Forssman antigen is a glycosphingolipid, a ceramide pentasaccharide with the structure GalNAcalpha1-->3GalNAcbeta1-->3Galalpha1-->4Galbeta1-->4Glc-->ceramide. Forssman-positive animals are capable of synthesizing this compound in tissues or in erythrocytes, in contrast to the Forssman-negative species, including humans, which are incapable of adding the last carbohydrate in the sequence of the Forssman antigen, namely alphaGalNAc. The Forssman glycolipid and its precursor globoside were examined in twenty-one samples of surgically extirpated gastrointestinal mucosa and tumors derived therefrom. The results revealed that a few patients had chemically and immunologically detectable levels of the Forssman glycolipid as a normal component of their gastrointestinal mucosa (F(+) population); in contrast, the majority of patients did not contain this glycolipid in their normal mucosa (F(-) population). Whereas the F(-) population included blood groups A, B, and O, the F(+) population did not correspond to blood group A. The Forssman status in tumors taken from the F(+) or F(-) population showed the following striking features: (i) all tumors derived from F(-) mucosa possessed Forssman glycolipid, whereas (ii) none of the tumors originating in F(+) mucosa contained Forssman glycolipid. Globoside, the immediate precursor of Forssman antigen, was distributed equally among F(+) and F(-) mucosa and the tumors derived therefrom. Thus, the expression of Forssman antigen in gastrointestinal mucosa appears akin to that of an isoantigen. Furthermore, the Forssman antigen that appears in tumors of the F(-) population could represent a human tumor-associated antigen. In view of the strong crossreactivity of Forssman antigen with blood group A determinants, the appearance of Forssman antigen in human tumors could be related to the "A-like antigen" (or "neo-A antigen") of human tumors reported previously [Hakomori, S., Koscielak, J., Black, K. J. & Jeanloz, R. W. (1967) J. Immunol. 98, 31-38; Häkkinen, I. (1970) J. Natl. Cancer Inst. 44, 1183-1193].

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Molecular genetic basis of the human Forssman glycolipid antigen negativity.

Publications

Molecular genetic basis of the human Forssman glycolipid antigen negativity.

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