HGNC Approved Gene Symbol: FUT6
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:5,830,408-5,839,702 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | [Fucosyltransferase 6 deficiency] | 613852 | 3 |
The alpha-1,3-fucosyltransferases constitute a large family of glycosyltransferases with a high degree of homology. The enzymes of this family comprise 3 main activity patterns called myeloid, plasma, and Lewis, based on their capacity to transfer alpha-L-fucose to distinct oligosaccharide acceptors, their sensitivity to N-ethylmaleimide inhibition, their cation requirements, and their tissue-specific expression patterns. The different categories of alpha-1,3-fucosyltransferases are sequentially expressed during embryo-fetal development. FUT6 encodes a 'plasma type' of alpha-1,3-fucosyltransferase (summary by Mollicone et al., 1994).
Weston et al. (1992) isolated and cloned a novel alpha(1,3)fucosyltransferase gene, which they designated FUT6, which encodes a deduced 358-amino acid protein. FUT6 shares 85% and 89% amino acid sequence identity with FUT3 (111100) and FUT5 (136835), respectively, but differs substantially in its acceptor substrate requirements.
Koszdin and Bowen (1992) amplified FUT6 by PCR of a squamous carcinoma cell line and a myeloid leukemia cell line.
Cameron et al. (1995) studied the tissue distribution of FUT6 by RT-PCR, RACE, and Northern blot analysis. They found that FUT6 was expressed at high levels as a 3.5-kb transcript in kidney and liver and as a 2.5-kb transcript in colon and liver. They identified alternate polyadenylation sites as well as splice variants resulting in deletion of the catalytic domain. By RT-PCR, Schnyder-Candrian et al. (2000) found FUT6 to be the major fucosyltransferase of human umbilical vein endothelial cells. Immunolocalization showed that FUT6 colocalizes with beta-4-galactosyltransferase-1 (B4GALT1; 137060) in compact juxtanuclear structures typical of the Golgi apparatus. Antibodies raised against another epitope of FUT6 localized the enzyme to Weibel-Palade bodies, endothelial storage granules.
By PCR analysis of somatic cell hybrid DNAs, Weston et al. (1992) demonstrated that the FUT6 gene is located on chromosome 19, where the Lewis blood group gene (FUT3; 111100) had long been known to be located.
McCurley et al. (1995) demonstrated that FUT5, FUT3, and FUT6 are located in the 19p13.3 region in an interval of about 40 kb. They are situated in close proximity and the direction of transcription of all 3 is toward the telomere. The organization may suggest coordinate regulation.
Weston et al. (1992) found that when FUT6 was transfected into mammalian cells, it was capable of directing expression of the Lewis x, sialyl Lewis x, and difucosyl sialyl Lewis x epitopes.
Koszdin and Bowen (1992) also showed that transfection of FUT6 cDNA into mammalian cells conferred alpha-1,3-fucosyltransferase activity to the cells, resulting in cell surface expression of Lewis x and sialyl Lewis x carbohydrates.
Whereas most humans express an alpha-1,3-fucosyltransferase in plasma, 9% of individuals on the isle of Java (Indonesia) do not express this enzyme. The Lewis negative phenotype is found on red cells of 95% of these FUT-deficient individuals, suggesting strong linkage disequilibrium between these 2 traits. To define a molecular basis for this plasma FUT deficiency (613852) and to determine which of 2 candidate human FUT genes, FUT5 (136835) and FUT6, encode this enzyme, Mollicone et al. (1994) cloned and analyzed alleles at these 2 loci from an Indonesian individual with fucosyltransferase deficiency. Single basepair changes were identified in the coding region of each gene, yielding 3 codon changes in FUT5 and 3 in FUT6. Only the changes in the FUT6 alleles inactivated the gene when tested by expression in transfected COS-1 cells. One of these inactivating changes was a missense mutation (glu247-to-lys) within the enzyme's catalytic domain. The other inactivating mutation, a nonsense tyr315-to-ter change, truncated the C terminus of the enzyme by 45 amino acids. The glu247-to-lys missense mutation was present in homozygous state in 9 plasma FUT-deficient individuals tested, whereas the nonsense mutation at tyrosine-315 was present in homozygous state in only 1 of these 9 persons. These results demonstrated that the alpha-1,3-fucosyltransferase activity in human plasma is encoded by the FUT6 gene and that the missense mutation within codon 247 of this gene is responsible for the Indonesian deficiency of this activity.
Brinkman-Van der Linden et al. (1996) found that all individuals with a homozygous gly739-to-ala FUT6 mutation showed no fucosylation of alpha-1-acid glycoprotein. The same result was found for alpha-1-antichymotrypsin and alpha-1-protease inhibitor. On the other hand, in all individuals with alpha-3-fucosyltransferase activity in the plasma, alpha-3-fucosylated glycoforms of the glycoproteins studied were found. Thus, their data suggested that the product of FUT6, but not of FUT3 or of FUT5, is responsible for the alpha-3-fucosylation of glycoproteins produced in liver and suggested that this organ is a major source of alpha-3-fucosyltransferase activity in plasma.
Pang et al. (1999) sequenced the 1080-bp coding region of the FUT6 gene in 161 individuals (322 chromosomes) drawn from 3 populations: 56 Africans (Xhosa), 52 European-Africans of South Africa, and 53 Japanese. In addition to 6 base substitutions previously reported, 11 new base substitutions and a single base insertion were found. They also identified 11 functional and 4 null alleles, of which 10 were novel. The allelic distributions of FUT6 were different among these 3 populations. The heterozygosity of FUT6 was 0.860, 0.699, and 0.632 in the 3 populations, respectively. Pang et al. (1999) suggested that the extensive DNA sequence diversity of FUT6 may make it suitable as a tool in genetic studies of modern human evolution.
Mollicone et al. (1994) demonstrated a glu247-to-lys (E247K) missense mutation in homozygous state as the apparent cause of fucosyltransferase deficiency in plasma (613852) found in 9% of individuals on the Isle of Java (Indonesia).
Brinkman-Van der Linden, E. C. M., Mollicone, R., Oriol, R., Larson, G., Van den Eijnden, D. H., Van Dijk, W. A missense mutation in the FUT6 gene results in total absence of alpha-3-fucosylation of human alpha-1-acid glycoprotein. J. Biol. Chem. 271: 14492-14495, 1996. [PubMed: 8662894] [Full Text: https://doi.org/10.1074/jbc.271.24.14492]
Cameron, H. S., Szczepaniak, D., Weston, B. W. Expression of human chromosome 19p alpha-(1,3)-fucosyltransferase genes in normal tissues: alternative splicing, polyadenylation, and isoforms. J. Biol. Chem. 270: 20112-20122, 1995. [PubMed: 7650030] [Full Text: https://doi.org/10.1074/jbc.270.34.20112]
Koszdin, K. L., Bowen, B. R. The cloning and expression of a human alpha-1,3 fucosyltransferase capable of forming the E-selectin ligand. Biochem. Biophys. Res. Commun. 187: 152-157, 1992. [PubMed: 1520296] [Full Text: https://doi.org/10.1016/s0006-291x(05)81472-x]
McCurley, R. S., Recinos, A., III, Olsen, A. S., Gingrich, J. C., Szczepaniak, D., Cameron, H. S., Krauss, R., Weston, B. W. Physical maps of human alpha(1,3)fucosyltransferase genes FUT3-FUT6 on chromosomes 19p13.3 and 11q21. Genomics 26: 142-146, 1995. [PubMed: 7782074] [Full Text: https://doi.org/10.1016/0888-7543(95)80094-3]
Mollicone, R., Reguigne, I., Fletcher, A., Aziz, A., Rustam, M., Weston, B. W., Kelly, R. J., Lowe, J. B., Oriol, R. Molecular basis for plasma alpha(1,3)-fucosyltransferase gene deficiency (FUT6). J. Biol. Chem. 269: 12662-12671, 1994. [PubMed: 8175676]
Pang, H., Koda, Y., Soejima, M., Schlaphoff, T., Du Toit, E. D., Kimura, H. Allelic diversity of the human plasma alpha(1,3)fucosyltransferase gene (FUT6). Ann. Hum. Genet. 63: 277-284, 1999. [PubMed: 10738539] [Full Text: https://doi.org/10.1046/j.1469-1809.1999.6340277.x]
Schnyder-Candrian, S., Borsig, L., Moser, R., Berger, E. G. Localization of alpha-1,3-fucosyltransferase VI in Weibel-Palade bodies of human endothelial cells. Proc. Nat. Acad. Sci. 97: 8369-8374, 2000. [PubMed: 10900002] [Full Text: https://doi.org/10.1073/pnas.97.15.8369]
Weston, B. W., Smith, P. L., Kelly, R. J., Lowe, J. B. Molecular cloning of a fourth member of a human alpha(1,3)fucosyltransferase gene family: multiple homologous sequences that determine expression of the Lewis x, sialyl Lewis x, and difucosyl sialyl Lewis x epitopes. J. Biol. Chem. 267: 24575-24584, 1992. Note: Erratum: J. Biol. Chem. 268: 18398 only, 1993. [PubMed: 1339443]