Molecular genetic analysis of the human Lewis histo-blood group system .2. Secretor gene inactivation by a novel single missense mutation A385T in Japanese nonsecretor individuals

The Lewis histo-blood group system comprises two major antigens, Lewis a and Lewis b. The Lewis b antigen is a product of two fucosyltransferases, the alpha(1,3/ 1,4)fucosyltransferase (Lewis enzyme; Fuc-TIII) encoded by the Lewis gene and an alpha(1,2)fucosyltransferase which is not required for synthesis of Lewis a antigen. An enzyme responsible for secreting ABH antigens into body secretions (secretor enzyme) is also one of alpha(1,2)fucosyltransferases. A candidate gene encoding secretor enzyme Sec2 gene was recently cloned by Rouquier, S., Lowe, J. B., Kelly, R. J., Fertitta, A. L., Lennon, G. G., and Giorgi, D. ((1995) J. Biol. Chem. 270, 4632-4639) and Kelly, R. J., Rouquier, S., Giorgi, D., Lennon, G. G., and Lowe, J. B. ((1995) J. BioL. Chem. 270, 4640-4649) who demonstrated a G428A nonsense mutation (Trp(143) to terminal codon) in Sec2 of nonsecretors. However, the G428A nonsense mutation discovered in the Sec2 gene of nonsecretors in an ethnic group other than Japanese was not found in any of 45 Japanese nonsecretors, whereas one Filipino who had been erroneously registered as a Japanese possessed the G428A mutation heterozygously. In order to explore the Sec2 gene of a Japanese population, we performed a molecular genetic analysis of the Sec2 gene on 226 Japanese individuals, 21 in a family study and 205 in a random sampling study. We discovered two novel mutations in the Sec2 gene, an A385T missense mutation (Ile(129) to Phe) that results in inactivation of Sec2-encoded alpha(1,2)fucosyltransferase and a C357T silent mutation which is irrelevant to amino acid substitution, in Japanese nonsecretors. The analysis of Japanese individuals using the polymerase chain reaction-restriction fragment length polymorphism method found three alleles in the Sec2 gene, the first having no mutation, the second having a C357T mutation, and the third having both C357T and A385T mutations, which we designated as Se1, Se2, and sej, respectively. Among 226 Japanese individuals, 40 having a Le(a+b-) phenotype and 5 having a Le(a-b-) nonsecretor phenotype were homozygous for sej/sej, whereas 149 having a Le(a-b+) phenotype and 32 having a Le(a-b-)-secretor phenotype possessed at least one Se1 or Se2. The frequencies of occurrence of Se1, Se2, and sej among 410 alleles examined in a random sample of 205 Japanese individuals were 15, 46, and 39%, respectively, indicating a rather wide distribution of the sej allele in the Japanese population. The results show that the Sec2 gene really encodes the secretor enzyme alpha(1,2)fucosyltransferase and indicate that a ethnic group-specific nonsense or missense point mutation in the Sec2 gene determines nonsecretor status. The phylogenic aspect and biological significance of the Se and Le genes are discussed.