Alternative titles; symbols
HGNC Approved Gene Symbol: FUT2
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:48,695,971-48,705,951 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | [Bombay phenotype, digenic] | 616754 | Autosomal recessive | 3 |
| {Norwalk virus infection, resistance to} | 3 | |||
| {Vitamin B12 plasma level QTL1} | 612542 | 3 |
The classic human secretor locus (Se) FUT2 encodes alpha-(1,2)fucosyltransferase, which regulates expression of the Lewis ABO(H) histo-blood group antigens on the surface of epithelial cells and in body fluids and determines the secretion status of the ABO antigens (see 616093). Secretor status of this polymorphic protein was used by Mohr (1951) to provide the first autosomal linkage in humans between secretor factor and the Lutheran blood group (see 111200) (summary by Hazra et al., 2008).
The secretor factor (Se) might be considered either a physiologic trait or an honorary blood group. The individual who is a so-called secretor has demonstrable ABH blood group antigen in the saliva and other body fluids; the nonsecretor does not. Secretor is dominant.
Rouquier et al. (1995) used the FUT1 cDNA to screen chromosome 19 cosmid libraries in search of the FUT2 gene. One cosmid was isolated that contained 2 distinct segments that cross-hybridized with FUT1.
Kelly et al. (1995) found that SEC2 encodes a predicted 332-amino acid polypeptide and a longer isoform that shares 68% sequence identity with the COOH-terminal 292 residues of human FUT1.
The secretor locus is linked to the Lutheran blood group locus (111200) and the myotonic dystrophy locus (DMPK; 605377). Coupled with the ability to determine the secretor status of the fetus from amniotic fluid (Harper et al., 1971), this linkage potentially allows prenatal diagnosis of myotonic dystrophy (DM; 160900). Oriol et al. (1981) suggested that the Se locus and the Hh (FUT1) locus (211100) may be closely linked. This is a condition of their model. Classically, the Se gene is considered to be a regulatory gene controlling expression of the structural gene H in external secretions. Under this hypothesis, Bombay (h-h) persons should not be able to express the Se gene. Oriol et al. (1981) analyzed statistically the 44 published Bombay pedigrees and concluded that in fact there is no suppression of Se in Bombay persons. Furthermore, they found a lod score of 12.9 at 1% recombination for linkage of Bombay and secretor. They suggested that Hh and Se are both structural genes, each coding for a 2-alpha-L-fucosyltransferase.
Le Pendu et al. (1982) presented evidence that the fucosyltransferase of epithelial origin, coded by the Se gene, is able to transform both type 1 and type 2 natural substrate, whereas the enzyme of mesodermal origin, coded by the H gene (mutant in the Bombay phenotype), works preferentially on type 2 natural substrate. The close linkage of the 2 genes is of interest. The possible existence of 2 alpha (1-to-2) fucosyltransferases was first suggested on the basis of stereochemical differences between the 2 precursor chains, types 1 and 2. Gedde-Dahl et al. (1984) found linkage of Se and APOE (107741)--peak lod score 3.3 at recombination fraction 0.08 in males and 1.36 at 0.22 in females, and linkage of APOE and Lu with lod score 4.52 at zero recombination in sexes combined. C3-APOE linkage gave lod score 4.0 at theta 0.18 in males but 0.04 at theta 0.45 in females. A summarizing map was given (Gedde-Dahl et al., 1984; see their Figure 3).
Kudo et al. (1996) reviewed briefly the biosynthetic pathways involved in synthesis of Lewis blood group antigens and secretion of ABH into saliva.
The Lutheran secretor linkage was the first autosomal linkage identified in man. It was first discovered by Mohr (1951) as a linkage of the Lutheran blood group and the 'recessive' Lewis blood group. This was recognized as the Lutheran-secretor linkage (Mohr, 1954) after the ingenious interpretation by Grubb (1953) of the interactions between the Lewis (FUT3) locus (111100) determining the presence/absence of Lewis substance in the saliva and on red cells and the Se locus determining secretion of ABH blood group substances in the saliva and Le(a) or Le(b) expression in red cells. Discovery of the secretor-C3 linkage in Mohr's department (Eiberg et al. (1983)) and the assignment of the C3 locus (120700) to chromosome 19 indicated that this historic linkage group is on that chromosome.
Rouquier et al. (1995) observed that a 100-kb cosmid contig, localized to 19q13.3 by fluorescence in situ hybridization, contained FUT1 and 2 FUT1-related sequences, termed SEC1 and SEC2 for secretor candidate 1 and 2. SEC1 and SEC2 were separated by 12 kb and were 65.5 kb and 35 kb apart, respectively, from the FUT1 gene. They concluded that SEC1 was a pseudogene with translational frameshifts and termination codons interrupting potential open reading frames that would otherwise share primary sequence similarity with FUT1.
Reguigne-Arnould et al. (1995) pointed out that 5 of the 7 fucosyltransferase genes cloned to that time had been mapped to 2 clusters, 1 with FUT1 and FUT2 on 19q and the other with FUT6 (136836), FUT3, and FUT5 (136835) on 19p. Linkage studies using microsatellite markers and comparison of genetic and physical maps suggested that FUT1 and FUT2 loci are located on 19q13.3.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Secretor/Nonsecretor Polymorphism
Kelly et al. (1995) found that approximately 20% of randomly selected individuals were apparently homozygous for an enzyme-inactivating W143X nonsense mutation (182100.0001) at the FUT2 locus, in correspondence with the frequency of the nonsecretor phenotype in most human populations. Furthermore, each of 6 unrelated nonsecretor individuals were apparently homozygous for this null allele.
Kudo et al. (1996) discussed the possibility of a selective advantage accounting for the development of different inactivating mutations of the SEC2 gene in different ethnic groups (see 182100.0002). The absence or presence of Lewis antigens, proven to be the product of Le and Se genes, and antigen expression in digestive organs, may be biologically much more important than expression in erythrocytes.
Koda et al. (1996) reviewed the molecular basis for the secretor-negative phenotype in Japanese. The nonsense mutation of the FUT2 gene, 428G-A (182100.0001), found in Caucasians and symbolized se1, was not found. They found, however, a missense mutation, 385A-T (182100.0002), designated se2, and 2 nonsense mutations (571C-T, se3, and 628C-T, se4) in the Japanese Se enzyme-deficient allele. In addition, Koda et al. (1996) found a fusion gene, which consisted of the 5-prime region of the pseudogene (FUT2P) and the 3-prime region of the functional FUT2 gene, as an Se enzyme-deficient allele (se5). The DNA sequence analysis of the fusion gene indicated that the crossover region corresponded to regions between bases 253 and 313 of the pseudogene and between bases 211 and 271 of the FUT2 gene. The findings suggested that the fusion gene was generated by homologous but unequal crossover. A population study on 141 randomly selected Japanese individuals indicated to Koda et al. (1996) that se2 is a common Se enzyme-deficient allele in the Japanese population and that secretor-deficient alleles are race-specific. Liu et al. (1999) investigated 5 populations from 3 ethnic groups in East Asia for the fusion gene. The fusion gene was found at a high frequency in 2 Japanese populations (0.0551 in Okinawa and 0.0792 in Akita), and at a very low frequency in a Korean population (0.0063 in Seoul). No individuals with the fusion gene were identified among 292 patients from 2 Chinese populations. The authors suggested that the fusion gene likely emerged from within the Japanese population, given its high frequency in the Japanese but rare occurrence in neighboring populations.
The common nonsecretor allele found in Caucasians (182100.0001) is virtually absent in Taiwanese and mainland Chinese. In several groups indigenous to Taiwan, the Le(a+b-) nonsecretor phenotype has been found, as reviewed by Yu et al. (1999).
Vitamin B12 Plasma Level Quantitative Trait Locus 1
Hazra et al. (2008) found a strong association between rs492602 in FUT2 and positive plasma vitamin B12 levels in a genomewide scan and an independent replication sample from the Nurses' Health Study. Women homozygous for the rs492602 G allele had higher B12 levels. This allele is in strong linkage disequilibrium with the FUT2 nonsecretor variant encoding W143X (182100.0001), suggesting a plausible mechanism for altered B12 absorption and plasma levels. This association was found in a cohort of healthy women of European descent.
Tanaka et al. (2009) performed a genomewide association analysis to identify genetic factors affecting circulating vitamin B12 levels and identified rs602662 in the FUT2 gene (p = 2.83 x 10(-20)) in Italians in the InCHIANTI (1,175 participants), SardiNIA (1,115 participants), and BLSA (640 participants) studies. The top locus was replicated in an independent sample from the 687 participants in the Progetto Nutrizione study.
Bombay Phenotype
Koda et al. (1997) found that a 725T-G transversion in FUT1 (211100.0004), which results in an amino acid change, leu242 to arg, and complete deletion of FUT2 (182100.0003) are responsible for the classic Bombay phenotype (see 616754).
Norwalk Virus Infection, Resistance to
Lindesmith et al. (2003) found that individuals who are homozygous for the FUT2 428G-A allele (182100.0001) in the ABH histo-blood group family do not express the H type-1 oligosaccharide ligand required for Norwalk virus binding. The FUT2 susceptibility allele is fully penetrant against Norwalk virus infection as none of these individuals developed an infection after challenge, regardless of dose. Of the susceptible population that encoded a functional FUT2 gene, a portion was resistant to infection, suggesting that a memory immune response or some other unidentified factor also affords protection from Norwalk virus infection.
Associations Pending Confirmation
For discussion of a possible association between variation in the FUT2 gene and susceptibility to Crohn disease, see 266600.
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).
Using gene targeting in embryonic stem cells, Domino et al. (2001) generated strains of mice that were deficient in Fut2. Fut2-null mice developed normally and exhibited no gross phenotypic abnormalities. Using immunohistochemistry, the authors observed that Fut2-null mice no longer exhibited the wildtype expression pattern of alpha(1,2)-fucosylated glycans in the uterine epithelium. However, normal fertility was observed. Domino et al. (2001) concluded that alpha(1,2)-fucosylated glycans play nonessential roles in blastocyst implantation or sperm function in mice.
Kelly et al. (1995) found that a nonsense mutation involving codon 143 (numbered from the putative initiator methionine of the short FUT2 protein) is responsible for the nonsecretor phenotype. See also Rouquier et al. (1995). The nonsense mutation was due to a G-to-A transition at nucleotide 428. However, the trp143-to-ter mutation found in ethnic groups other than Japanese was not found in any of 45 Japanese nonsecretors. Instead, 2 novel mutations, a C-to-T transition at nucleotide 357 and an A-to-T transversion at nucleotide 385 were found in Japanese nonsecretors. The 357C-T mutation was silent insofar as amino acid substitution was concerned; the 385A-T missense mutation (182100.0002) resulted in inactivation of the alpha(1,2)fucosyltransferase.
Vitamin B12 Plasma Level Quantitative Trait Locus 1
Hazra et al. (2008) found that 3 single-nucleotide polymorphisms in the FUT2 gene, including rs601338, which encodes the W143X variant, are in strong linkage disequilibrium and are strongly associated with plasma levels of vitamin B12 as a quantitative trait (B12QTL1; 612542). Hazra et al. (2008) considered the W143X polymorphism to be a plausible causal variant for this association.
Norwalk Virus Infection, Resistance to
Lindesmith et al. (2003) found that individuals who are homozygous for the FUT2 428G-A allele in the ABH histo-blood group family do not express the H type-1 oligosaccharide ligand required for Norwalk virus binding. The FUT2 susceptibility allele is fully penetrant against Norwalk virus infection as none of these individuals developed an infection after challenge, regardless of dose. Of the susceptible population that encoded a functional FUT2 gene, a portion was resistant to infection, suggesting that a memory immune response or some other unidentified factor also affords protection from Norwalk virus infection.
In the SE gene, designated SEC2 by Rouquier et al. (1995), Kudo et al. (1996) found homozygosity for an A-to-T transversion at nucleotide 385, resulting in a missense substitution ile129-to-phe in all Japanese nonsecretor individuals. They referred to the mutant allele in Japanese nonsecretors as sej; sej/sej homozygosity accounted for more than 15% of the Japanese population. The inactivated sej allele had a frequency of 39% in the Japanese. Kudo et al. (1996) discussed the possibility of a selective advantage accounting for the development of different inactivating mutations of the SEC2 gene in different ethnic groups.
In 3 unrelated individuals with the Bombay phenotype (see 616754), Koda et al. (1997) found that a 725T-G transversion in FUT1 (211100.0004), which results in an amino acid change, leu242 to arg, and complete deletion of FUT2 were responsible for the classic Bombay phenotype. The individuals lacked the H antigen not only on blood cells but also in saliva, which prompted Koda et al. (1997) to investigate the FUT2 gene in these persons. The mutations in both genes were homozygous. The results of analyses of FUT1 and FUT2 by Koda et al. (1997) suggested that the homozygosity for these 2 unusual and linked genetic mutations is common in individuals with the classic Bombay phenotype.
Koda et al. (2000) isolated the junction region of the deletion of FUT2 and found evidence that the deletion was generated by Alu-Alu recombination.
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