Molecular Genetic Analysis of the Human Lewis Histo-blood Group System

Abstract

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 α(1,3/1,4)fucosyltransferase (Lewis enzyme; Fuc-TIII) encoded by the gene and an α(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 α(1,2)fucosyltransferases. A candidate gene encoding secretor enzyme gene was recently cloned by Rouquier, S., Lowe, J. B., Kelly, R. J., Fertitta, A. L., Lennon, G. G., and Giorgi, D. ((1995) 270, 4632-4639) and Kelly, R. J., Rouquier, S., Giorgi, D., Lennon, G. G., and Lowe, J. B. ((1995) 270, 4640-4649) who demonstrated a G428A nonsense mutation (Trp to terminal codon) in of nonsecretors. However, the G428A nonsense mutation discovered in the 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 gene of a Japanese population, we performed a molecular genetic analysis of the gene on 226 Japanese individuals, 21 in a family study and 205 in a random sampling study. We discovered two novel mutations in the gene, an A385T missense mutation (Ile to Phe) that results in inactivation of -encoded α(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 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 , , and , respectively. Among 226 Japanese individuals, 40 having a Le(a+b-) phenotype and 5 having a Le(a-b-) nonsecretor phenotype were homozygous for , whereas 149 having a Le(a-b+) phenotype and 32 having a Le(a-b-)-secretor phenotype possessed at least one or . The frequencies of occurrence of , , and 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 allele in the Japanese population. The results show that the gene really encodes the secretor enzyme α(1,2)fucosyltransferase and indicate that a ethnic group-specific nonsense or missense point mutation in the gene determines nonsecretor status. The phylogenic aspect and biological significance of the and genes are discussed.