SEQUENCE AND EXPRESSION OF A CANDIDATE FOR THE HUMAN SECRETOR BLOOD-GROUP ALPHA(1,2)FUCOSYLTRANSFERASE GENE (FUT2) - HOMOZYGOSITY FOR AN ENZYME-INACTIVATING NONSENSE MUTATION COMMONLY CORRELATES WITH THE NON-SECRETOR PHENOTYPE

Synthesis of soluble A, B, H, and Lewis b blood group antigens in huma ns is determined by the Secretor (Se) (FUT2) blood group locus. Geneti c, biochemical, and molecular analyses indicate that this locus corres ponds to an alpha(1,2)fucosyltransferase gene distinct from the geneti cally-linked H blood group alpha(1,2)fucosyltransferase lo cus. The ac companying paper (Rouquier, S., Lowe, J, B., Kelly, R. J., Fertitta, A L., Lennon, G. G., and Giorgi, D. (1995) J. Biol. Chem. 270, 4632-463 9) describes the molecular cloning and mapping of two human DNA segmen ts that are physically linked to, and cross-hybridize with, the H locu s. We present here an analysis of these two new DNA segments. One of t hese, termed Sec1, is a pseudogene, because translational frameshifts and termination codons interrupt potential open reading frames that wo uld otherwise share primary sequence similarity with the H alpha(1,2)f ucosyltransferase. The other DNA segment, termed Seca, predicts a 332- amino acid-long polypeptide, and a longer isoform, that share 68% sequ ence identity with the COOH-terminal 292 residues of the human H blood group alpha(1,2)fucosyltransferase. Sec2 encodes an alpha(1,2)fucosyl transferase with catalytic properties that mirror those ascribed to th e Secretor locus-encoded alpha(1,2)fucosyltransferase. Approximately 2 0% of randomly-selected individuals were found to be apparently homozy gous for an enzyme-inactivating nonsense allele (Trp(143) --> ter) at this locus, in correspondence to the frequency of the non-secretor phe notype in most human populations. Furthermore, each of six unrelated n on-secretor individuals are also apparentry homozygous for this null a llele. These results indicate that Seca corresponds to the human Secre tor blood group locus (FUT2) and indicate that homozygosity for a comm on nonsense allele is responsible for the nonsecretor phenotype in man y non-secretor individuals.