|Blood Group Antigen Gene Mutation Database|
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Lewis Blood Group System
Gene locus - FUT3 (Lewis); FUT2 (Secretor); FUT6
The Lewis determinants are structurally related to determinants of the ABO and the H/h blood group systems. They are assembled by sequential addition of specific monosaccharides onto terminal saccharide precursor chains on glycolipids or glycoproteins. On the erythrocyte surface they reside on glycolipids. In contrast to the other blood group antigens, the synthesis of these glycolipids does not occur in erythroid tissues, but they are acquired by the erythrocyte membranes form other tissues through circulating lipoproteins.
The synthesis of the epitopes is dependent on the interaction of two different fucosyltransferases, products of two different loci: FUT2 or the secretor (Se) locus that encodes the alpha (1,2) fucosyltransferase (FUT2)(see the H/h blood group system), and the FUT3 locus that encodes the alpha (1/3,1/4 fucosyltransferase (FUT3). The final oligosacharide products are the result of the action of these enzymes on the same oligosaccharide precursor substrates of type 1 configuration: Gal beta 1-3 GlcNAc beta-R. An important property of FUT3 should be noted - namely, it can use as substrates both type 1 and type 2 carbohydrate chains resulting in either alpha 1,3 or alpha 1,4 linkages (hence, the FUT3 enzyme is also known as alpha 3/4-Fuc-T).
As stated above, Lewis (Le) a and b epitopes are both products of substrates in type 1 configuration, whereas Le X and Y are the equivalent products when the substrates are in type 2 configuration (see below). Fucosylation by FUT3 gives rise to the Le a epitope, whereas the action of both enzymes results in Le b. Thus, the Le a epitope results from the addition by FUT3 of a fucose in an alpha 1-4 linkage to the GlcNAc on the unsubstituted precursor substrate. This product cannot be further glycosylated, and is the main antigen found in ABH nonsecretor individuals whose Lewis phenotype, therefore, is Le(a+b-).
The Le b epitope occurs when type 1 H epitope generated by the FUT2 locus, or the precursor substrate containing an alpha (1-2)-fucose linked to the Gal, is used as a substrate by FUT3. It is the main epitope found in ABH secretor individuals and is responsible for their Le(a-b+) phenotype.
Clearly, the genotype of an individual at the FUT2 and FUT3 loci determines the Lewis phenotype. In the presence of FUT2 alleles that express type 1 H determinants, the phenotype will be Le (a-b+), but individuals in whom the FUT2 gene is not expressed, it will be Le(a+b-). A Le(a+b+) phenotype may occur in individuals in whom the expression of H is decreased due to a mutation in the FUT2 gene (385A>T). This phenotype may also occur due to incomplete fucosylation of type H precursor sites. Failure to express FUT3 will result in a Lewis null phenotype [Le(a-b-)], irrespective of the Secretor status. However, one should note that the latter phenotype may also be observed upon the absence of Le glycolipids from the membrane, as may occur in patients with certain cancer or other conditions.
The FUT3 genes resides on chromosome 19p13.3, in a cluster with two other homologous genes of the family, FUT5 and FUT6, in the gene order FUT6-FUT3-FUT5 (Reguigne-Arnould et al.). A relatively significant number of variants of the FUT6 gene has been documented and they are listed here following the FUT3 alleles.
Function of proteins
Primary gene product of FUT3 functional alleles is an alpha(1,3/1,4) fucosyltransferase that transfers a fucose to a N-acetylglucosamine in either an alpha 1,4 linkage if the N-acetylglucosamine is located on a type 1 precursor, or in an alpha 1,3 linkage if it resides on a type 2 precursor. The former configuration is required for the expression of Lewis a or b antigens, wheras the latter is typical of Lewis X and Y. The function of Le a or Le b antigens is not clear but no apparent pathological consequences appear in Lewis null individuals. In sialylated forms they may serve as ligands for E-selectins. Their function in tumor tissues is not clear but they serve as tumor markers. The Le x and sLe x structures play an important role in adhesion phenomena in development and adult tissues.
As noted above the Lewis antigens are not synthesized in erythocyte progenitors. The glycosphingolipids that carry the antigenic Le-a or Le-b epitopes circulate in plasma bound to serum lipoproteins or in form of aqueous dispersions; they become adsorbed to the erythrocyte by a passive adsorption process. That is why their levels may vary; they are usually not detected on erythocytes of newborns but attain adult levels by the age of two. Also their red cell phenotype may become altered in disease or other conditions, such as pregnancy. It appears that the tissue-specific expression pattern of the FUT3 closely corresponds to that of the FUT2; the synthesis of Lewis glycans occurs predominantly in exocrine epithelial cells, mostly of endodermal origin. The digestive track is probably a major, but not exclusive, site of Lewis plasma glycolipid synthesis. They are expressed in colon and pancreas and a number of malignant tumors. Lewis and related antigens may occur as free oligosaccharides in milk and urine or may be protein-bound in a variety of tissues.
None reported; absence of determinants as observed in true (not caused by failure to adsorb from plasma) Lewis null individuals does not cause disease. Thus, the absence of an active FUT3 enzyme may not be required for a normal physiological function, and fucosylation of essential substrates may be carried out by the other FUTs of the family. However, the Le-b glycan may be a receptor for Helicobacter pylori (Boren et al.). Lewis antigens are absent in patients suffering from the leukocyte adhesion deficiency syndromes, LADI or LADII. In the latter case the absence of the epitopes is due to a mutation in the GDP-fucose transporter (Luhn et al.; Hirschberg CB)
In many ways the Lewis blood group system is analogous to the ABO and Hh blood group systems: 1) the antigens are indirect gene products and the epitopes are based on specific glycan structures. The structures result from the action of specific glycosyltransferases. 2) Both the ABO and Lewis systems are dependent on the H antigens to serve as precursor substrates that give rise to the A, B or Lewis epitopes. 3) The epitopes of the ABO and Lewis systems both depend on the interaction of products of two genetically independent loci, yet the polymorphisms observed in the population have a different molecular basis: in the ABO system two different alleles of the same gene result in either a N-acetylgalactosamine transferase or a galactose transferase ultimately responsible for the difference between the A and B epitopes, whereas the difference between Le a and Le b epitopes depends primarily on the status of the product of the FUT2 (secretor or Se) locus: if that enzyme is active (secretor status) the fucosylation of the precursor substrate by FUT3 will result in the Le b epitope whereas if the enzyme is inactive (nonsecretor) the precursor substrate for FUT3 will not be fucosylated and the epitope, with a single fucose introduced by FUT3, will be Le a. In the case of an inactive FUT3 both epitopes will be obliterated and the phenotype will be Le(a-b-), irrespective of the activity state of FUT2. Thus, the introduction by FUT2 of the alpha 1,2 fucose in the absence of an alpha 1,4 adjacent fucose does not result in the Lewis epitope.
As noted, the expression of Lewis epitopes on the erythrocytes is dependent on adsorption from plasma of Lewis-bearing glycolipids. Thus, the Lewis negative phenotype may not occur uniquely as a result of an inactive allele, but may result from several other causes such as a failure of adsorption to the erythocyte or presence of an allele whose product is less active or may be selectively inactive towards glycolipid precursor substrates. Because other members of the fucosyltransferases family may fucosylate type 2 precursor substrates resulting in Le X and Le Y epitopes, the known alleles of FUT6 and FUT7 are included in the list of alleles because they give rise, respectively, to plasma or leukocyte alpha-3 fucosyltransferase. While most humans express FUT6 enzyme in plasma, 9% of individuals on the isle of Java (Indonesia) do not express this enzyme. It is of interest that 95% of plasma FUT6-deficient individuals have Lewis negative phenotype on red cells (in these subjects the status of FUT3 is not clear as yet), suggesting strong linkage disequilibrium between FUT3 and FUT6 genes. Concerning FUT7, so far, only a single variant allele was documented, occurring with an estimated frequency of ~1% in the population.
In the list of alleles, the following sequences (accession numbers) are used as reference: X53578 for Fut3, M98825 for Fut6, U11282 for Fut7.
When searching for a particular allele, use "name" if DNA alteration is known or, if you wish to search by phenotype or the designation used by author, use "alias" (see "Details").
Other database IDs and links
The FUT2 locus and its common and rare alleles are described under H/h blood group system.
Dr. Rafael Oriol, INSERM U504, Paris South University XI, 16 Av., Paul Vaillant-Couturier, 94807 Villejuif, France; email: firstname.lastname@example.org
Dr.Hisashi Narimatsu, Laboratory of Gene Function Analysis, Institute of Molecular and Cell Biology, National Institute of Advanced Industrial Science and Technology (AIST), Open Space Laboratory C-2,1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan; Tel : 81-298-61-3200; Fax: 81-298-61-3201; email: H.email@example.com
Contributors for specific alleles are listed with the alleles.
Updated 2009-01-26 17:58:25.917