Alternative titles; symbols
HGNC Approved Gene Symbol: FUT3
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:5,842,888-5,857,122 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | [Blood group, Lewis] | 618983 | 3 |
The primary antigens of the Lewis blood group system (618983), Le(a) and Le(b), are not synthesized by red cells but are introduced into the red cell membrane from plasma. FUT3 encodes an alpha-1,4-L-fucosyltransferase that catalyzes the addition of a fucose residue to the H antigen (see FUT2, 182100) to produce Le(b) or to the precursor of H to produce Le(a). FUT3 can also convert A antigen to ALe(b) and B antigen to BLe(b) (see ABO, 110300) (summary by Daniels, 2002).
From linkage studies using microsatellite markers, Reguigne-Arnould et al. (1995) concluded that the FUT3 gene is in a cluster with FUT6 (136836) and FUT5 (136835) on chromosome 19p13.3. The following gene order was deduced: 19pter--D19S216--FUT6--FUT3--FUT5--D19S567--cen.
Grollman et al. (1969) showed that Lewis-negative women lacked a specific fucosyltransferase present in the milk of Lewis-positive women. The enzyme appeared to be required for synthesis of the structural determinants of both Le(a) and Le(b) specificity. The same enzyme was involved in synthesis of milk oligosaccharides, because 2 oligosaccharides containing the relevant linkage were absent from milk of Lewis-negative women. Grubb (1953) provided the ingenious interpretation of the interactions between the Les locus determining presence/absence of Lewis substance in the saliva and on red cells and the Se locus (FUT2; 182100) determining secretion of ABH blood group substances in the saliva and Le(a) or Le(b) expression in red cells.
Boren et al. (1993) determined that the Le(b) antigen is an epithelial receptor for H. pylori (see 600263). The H. pylori adhesin that binds Le(b) is BabA, which is encoded by babA2, a strain-specific gene (Peek, 2003). H. pylori strains isolated from patients with gastric cancer more commonly possessed this gene than did strains isolated from patients with gastritis alone.
Nishihara et al. (1994) found that all le alleles had a 59T-G mutation, whereas none of the Le alleles did. The le alleles were divided into 2 subtypes, le1, having a 508G-A mutation (G170S; 111100.0001), and le2, having a 1067T-A mutation. The 1067T-A mutation reduced the enzyme activity less than 10%, whereas the 508G-A mutation in the catalytic domain made the enzyme completely inactive. The frequency of Le, le1, and le2 in the Japanese population was found to be 66%, 30%, and 4%, respectively.
In transfusion medicine, it has been found that some individuals who type as Lewis-positive on erythrocytes can change their erythrocyte phenotype to Lewis-negative during diseases or during pregnancy. Orntoft et al. (1996) noted that these patients have been named non-genuine Lewis-negative individuals as they have alpha-1-4 fucosyltransferase activity in saliva. Due to this phenomenon, the Lewis-negative phenotype is more common among cancer patients (approximately 20%) than among healthy individuals (approximately 8%). Orntoft et al. (1996) examined the mutational spectrum of the Lewis gene in Denmark and found 6 different mutations. Five, 59T-G (L20R), 202T-C (W68R), 314C-T (T105M), 508G-A (G170S; 111100.0001), and 1067T-A (I356K), were frequent, and 1, 445C-A (L146M), was only detected in 1 of 40 individuals. The authors demonstrated that the nucleotide 202 and 314 mutations were located on the same allele. COS-7 cells transfected with an allele having the 202/314 mutations lacked enzyme activity. Lewis-negative patients, whose erythrocytes converted from Lewis-positive to Lewis-negative during their disease, showed FUT3 heterozygosity significantly more often than did others (p less than 0.05).
Pang et al. (1998) identified 5 novel missense mutations in the FUT3 gene in African (Xhosa) and Caucasian subjects in South Africa.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Falk et al. (1995) created transgenic mice with the human Le gene and showed that Helicobacter pylori, a causative agent of gastric disorders, attached to gastric epithelial cells in the transgenic mice but not in their normal littermates. This implies that Le/Le individuals may have an advantage in avoiding H. pylori infection (600263).
Koda et al. (1993) examined the expression of Lewis fucosyltransferase mRNA in gastric mucosa from 2 Lewis-positive and 2 Lewis-negative individuals (see 618983). Northern blot analysis demonstrated that levels of mRNA were similar in the 2 different types. In the Le(-) gastric mucosa, the sequence of cDNA showed 2 single-base substitutions: G for T at position 59 and A for G at position 508 from the A of the initiation codon. These substitutions predicted 2 amino acid changes: arg for leu at position 20 (L20R) and ser for gly at position 170 (G170S) from the N terminus. To determine whether either or both of these base substitutions was responsible for the Le(-) phenotype, Koda et al. (1993) constructed chimera cDNAs and expressed them in COS cells. Those COS cells transfected with a chimera cDNA containing a mutation of the nucleotide 508 did not express Lewis antigen, whereas those cells transfected with a chimeric cDNA containing the nucleotide 59 mutation expressed Lewis antigen, indicating that a single-base change from G to A at position 508 is responsible for the Le(-) phenotype. The G-to-A transition at position 508 created a new site for the restriction enzyme PvuII. One of the Le(-) individuals was shown to be homozygous for the PvuII site; the other Le(-) individual was heterozygous for the site, suggesting the presence of other Le(-) allele(s).
Boren, T., Falk, P., Roth, K. A., Larson, G., Normark, S. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 262: 1892-1895, 1993. [PubMed: 8018146] [Full Text: https://doi.org/10.1126/science.8018146]
Daniels, G. Human Blood Groups. (2nd ed.) Oxford: Blackwell 2002.
Falk, P. G., Bry, L., Holgersson, J., Gordon, J. I. Expression of a human alpha-1,3/4-fucosyltransferase in the pit cell lineage of FVB/N mouse stomach results in production of Leb-containing glycoconjugates: a potential transgenic mouse model for studying helicobacter pylori infection. Proc. Nat. Acad. Sci. 92: 1515-1519, 1995. [PubMed: 7878011] [Full Text: https://doi.org/10.1073/pnas.92.5.1515]
Grollman, E. F., Kobata, A., Ginsburg, V. An enzymatic basis for Lewis blood types in man. J. Clin. Invest. 48: 1489-1494, 1969. [PubMed: 5796361] [Full Text: https://doi.org/10.1172/JCI106115]
Grubb, R. Zur Genetik des Lewis-Systems. Naturwissenschaften 21: 560-561, 1953.
Koda, Y., Kimura, H., Mekada, E. Analysis of Lewis fucosyltransferase genes from the human gastric mucosa of Lewis-positive and -negative individuals. Blood 82: 2915-2919, 1993. [PubMed: 8219240]
Nishihara, S., Narimatsu, H., Iwasaki, H., Yazawa, S., Akamatsu, S., Ando, T., Seno, T., Narimatsu, I. Molecular genetic analysis of the human Lewis histo-blood group system. J. Biol. Chem. 269: 29271-29278, 1994. [PubMed: 7961897]
Orntoft, T. F., Vestergaard, E. M., Holmes, E., Jakobsen, J. S., Grunnet, N., Mortensen, M., Johnson, P., Bross, P., Gregersen, N., Skorstengaard, K., Jensen, U. B., Bolund, L., Wolf, H. Influence of Lewis alpha-1-3/4-L-fucosyltransferase (FUT3) gene mutations on enzyme activity, erythrocyte phenotyping, and circulating tumor marker sialyl-Lewis a levels. J. Biol. Chem. 271: 32260-32268, 1996. [PubMed: 8943285] [Full Text: https://doi.org/10.1074/jbc.271.50.32260]
Pang, H., Liu, Y., Koda, Y., Soejima, M., Jia, J., Schlaphoff, T., du Toit, E. D., Kimura, H. Five novel missense mutations of the Lewis gene (FUT3) in African (Xhosa) and Caucasian populations in South Africa. Hum. Genet. 102: 675-680, 1998. [PubMed: 9703429] [Full Text: https://doi.org/10.1007/s004390050760]
Peek, R. M., Jr. Personal Communication. Nashville, Tenn. 2/27/2003.
Reguigne-Arnould, I., Couillin, P., Mollicone, R., Faure, S., Fletcher, A., Kelly, R. J., Lowe, J. B., Oriol, R. Relative positions of two clusters of human alpha-L-fucosyltransferases in 19q (FUT1-FUT2) and 19p (FUT6-FUT3-FUT5) within the microsatellite genetic map of chromosome 19. Cytogenet. Cell Genet. 71: 158-162, 1995. [PubMed: 7656588] [Full Text: https://doi.org/10.1159/000134098]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.