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
T. Kudo et al., 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 Journal of biological chemistry, 271(16), 1996, pp. 9830-9837
The Lewis histo-blood group system comprises two major antigens, Lewis
a and Lewis b. The Lewis b antigen is a product of two fucosyltransfe
rases, 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 a
lso one of alpha(1,2)fucosyltransferases. A candidate gene encoding se
cretor enzyme Sec2 gene was recently cloned by Rouquier, S., Lowe, J.
B., Kelly, R. J., Fertitta, A. L., Lennon, G. G., and Giorgi, D. ((199
5) J. Biol. Chem. 270, 4632-4639) and Kelly, R. J., Rouquier, S., Gior
gi, D., Lennon, G. G., and Lowe, J. B. ((1995) J. BioL. Chem. 270, 464
0-4649) who demonstrated a G428A nonsense mutation (Trp(143) to termin
al codon) in Sec2 of nonsecretors. However, the G428A nonsense mutatio
n discovered in the Sec2 gene of nonsecretors in an ethnic group other
than Japanese was not found in any of 45 Japanese nonsecretors, where
as one Filipino who had been erroneously registered as a Japanese poss
essed the G428A mutation heterozygously. In order to explore the Sec2
gene of a Japanese population, we performed a molecular genetic analys
is 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 re
sults in inactivation of Sec2-encoded alpha(1,2)fucosyltransferase and
a C357T silent mutation which is irrelevant to amino acid substitutio
n, in Japanese nonsecretors. The analysis of Japanese individuals usin
g the polymerase chain reaction-restriction fragment length polymorphi
sm method found three alleles in the Sec2 gene, the first having no mu
tation, the second having a C357T mutation, and the third having both
C357T and A385T mutations, which we designated as Se1, Se2, and sej, r
espectively. Among 226 Japanese individuals, 40 having a Le(a+b-) phen
otype and 5 having a Le(a-b-) nonsecretor phenotype were homozygous fo
r 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 freque
ncies of occurrence of Se1, Se2, and sej among 410 alleles examined in
a random sample of 205 Japanese individuals were 15, 46, and 39%, res
pectively, indicating a rather wide distribution of the sej allele in
the Japanese population. The results show that the Sec2 gene really en
codes the secretor enzyme alpha(1,2)fucosyltransferase and indicate th
at a ethnic group-specific nonsense or missense point mutation in the
Sec2 gene determines nonsecretor status. The phylogenic aspect and bio
logical significance of the Se and Le genes are discussed.