* 211100

FUCOSYLTRANSFERASE 1; FUT1


Alternative titles; symbols

H ANTIGEN
Hh


HGNC Approved Gene Symbol: FUT1

Cytogenetic location: 19q13.33     Genomic coordinates (GRCh38): 19:48,748,011-48,755,358 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.33 [Bombay phenotype] 616754 AR 3

TEXT

Cloning and Expression

Larsen et al. (1990) cloned and sequenced a gene which they showed encodes the H blood group antigen. When expressed in COS-1 cells, the cDNA directed expression of cell surface H structures and a cognate alpha-(1,2)FT activity with properties analogous to the human H blood group alpha-(1,2)FT. The cDNA predicted a 365-amino acid polypeptide.


Gene Function

All human bloods, with exceedingly rare exceptions, carry the red cell H antigen. It is present in greatest amount on type O red cells and least on type A1B cells. The H antigen is an intermediate stage in a series of syntheses ending, in the presence of the A or B genes, in the production of the corresponding A and B antigens.

Oriol et al. (1981) suggested that Hh and Se (FUT2; 182100) are both structural genes, each coding for a 2-alpha-L-fucosyltransferase. The same group (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 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.

Le Pendu et al. (1985) concluded that there are at least 2 distinct alpha-2-L-fucosyltransferases in human serum; the enzymatic activity in H-deficient secretor serum may be the product of the Se gene and the enzymatic activity found in the H-normal nonsecretor serum could be the product of the H gene. These conclusions are consistent with the close linkage of the H and Se genes, which may have arisen by gene duplication from a common ancestral gene.


Mapping

Oriol et al. (1981) found a lod score of 12.9 at 1% recombination for linkage of Se and H.

By Southern blot analysis, Larsen et al. (1990) mapped the gene encoding the H blood group antigen to chromosome 19.

From comparison of the genetic and physical maps and linkage studies using microsatellite markers, Reguigne-Arnould et al. (1995) concluded that the tightly linked FUT1-FUT2 genes are located on 19q13.3.


Molecular Genetics

In an individual with the classic Bombay phenotype (616754), Kelly et al. (1994) identified homozygosity for a nonsense mutation in the FUT1 gene (Y316X), predicting a mutant protein missing the 50 C-terminal amino acids of the wildtype enzyme. In an individual with a para-Bombay phenotype (see 616754), they identified compound heterozygous mutations in the FUT1 gene (L164H, 211100.0002 and Q276X, 211100.0003). The mutation segregated with the phenotype in both families.

In 3 unrelated individuals with the classic Bombay phenotype, Koda et al. (1997) identified a heterozygous mutation in the FUT1 gene (L242R; 211100.0004) on one allele and complete deletion of the FUT2 gene (182100.0003) on the other.

Fernandez-Mateos et al. (1998) identified a homozygous missense mutation (H117Y; 211100.0005) in the FUT1 gene as the cause of the para-Bombay phenotype (Reunion variant) on Reunion Island.


Animal Model

Using gene targeting in embryonic stem cells, Domino et al. (2001) generated mice that were deficient in Fut1. Fut1-null mice developed normally and exhibited no gross phenotypic abnormalities. Using immunohistochemistry, the authors observed that Fut1-null mice were deficient in epididymal cell surface alpha(1,2)-fucosylated glycans expressed by wildtype mice. However, normal fertility was observed. They concluded that alpha(1,2)-fucosylated glycans play nonessential roles in blastocyst implantation or sperm function in mice.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 BOMBAY PHENOTYPE

FUT1, TYR316TER
  
RCV000012922

Kelly et al. (1994) sequenced approximately 6.5 kb of genomic DNA encompassing a wildtype FUT1 allele and the corresponding region in an allele from a patient with the Bombay phenotype (616754). The Bombay allele differed from the wildtype allele at 6 positions. Three of these single nucleotide differences were in the gene's single intervening sequence, 1 was within the coding region, and 2 were in the 3-prime untranslated region. The sequence difference in the coding region was a nonsense mutation that created a termination codon corresponding to amino acid 316 of the wildtype alpha(1,2)FT: tyr316-to-ter (Y316X). This sequence alteration predicted a mutant polypeptide that is missing the 50 C-terminal amino acids of the wildtype enzyme. The mutation was present in homozygous state. To confirm that the Y316X mutation inactivates the allele, Kelly et al. (1994) moved this DNA sequence difference and each of the others into the wildtype sequence background and tested for function by transfection into an alpha(1,2)FT-deficient mammalian host, namely, COS-1 cells. The wildtype construct encoded a substantial amount of transferase activity, whereas the Bombay construct generated no enzyme activity. By contrast, vectors containing each of the other DNA sequence differences expressed normal levels of transferase activity in transfected cells.


.0002 PARA-BOMBAY PHENOTYPE

FUT1, LEU164HIS
  
RCV000012923

In an individual with the para-Bombay phenotype (see 616754), Kelly et al. (1994) found compound heterozygosity for 2 mutations of the FUT1 gene: leu164-to-his (L164H) and gln276-to-ter (Q276X; 211100.0003).


.0003 PARA-BOMBAY PHENOTYPE

FUT1, GLN276TER
  
RCV000012924

For discussion of the gln276-to-ter (Q276X) mutation in the FUT1 gene that was found in compound heterozygous state in an individual with the para-Bombay phenotype by Kelly et al. (1994), see 211100.0002.


.0004 BOMBAY PHENOTYPE, DIGENIC

BOMBAY PHENOTYPE
FUT1, LEU242ARG
  
RCV000012925...

In 3 unrelated individuals with the classic Bombay phenotype (616754), Koda et al. (1997) identified that a 725T-G transversion in the FUT1, resulting in a leu242-to-arg (L242R) substitution, and complete deletion of the FUT2 gene (182100.0003).

By sequencing the FUT1 gene in patients from Reunion Island with the Bombay phenotype (616754), Fernandez-Mateos et al. (1998) identified homozygosity for the L242R mutation.


.0005 PARA-BOMBAY PHENOTYPE

FUT1, HIS117TYR
  
RCV000207394

By sequencing the FUT1 gene in patients from Reunion Island with the para-Bombay phenotype (see 616754), Fernandez-Mateos et al. (1998) identified a homozygous c.349C-T transition, resulting in a his117-to-tyr (H117Y) substitution. Family segregation and transfection experiments demonstrated that this mutation is responsible for the weak H-deficient Reunion variant.


REFERENCES

  1. Domino, S. E., Zhang, L., Gillespie, P. J., Saunders, T. L., Lowe, J. B. Deficiency of reproductive tract alpha(1,2)fucosylated glycans and normal fertility in mice with targeted deletions of the FUT1 or FUT2 alpha(1,2)fucosyltransferase locus. Molec. Cell. Biol. 21: 8336-8345, 2001. [PubMed: 11713270, images, related citations] [Full Text]

  2. Fernandez-Mateos, P., Cailleau, A., Henry, S., Costache, M., Elmgren, A., Svensson, L., Larson, G., Samuelsson, B. E., Oriol, R., Mollicone, R. Point mutations and deletion responsible for the Bombay H null and the Reunion H weak blood groups. Vox Sang. 75: 37-46, 1998. [PubMed: 9745152, related citations]

  3. Kelly, R. J., Ernst, L. K., Larsen, R. D., Bryant, J. G., Robinson, J. S., Lowe, J. B. Molecular basis for H blood group deficiency in Bombay (Oh) and para-Bombay individuals. Proc. Nat. Acad. Sci. 91: 5843-5847, 1994. [PubMed: 7912436, related citations] [Full Text]

  4. Koda, Y., Soejima, M., Johnson, P. H., Smart, E., Kimura, H. Missense mutation of FUT1 and deletion of FUT2 are responsible for Indian Bombay phenotype at ABO blood group system. Biochem. Biophys. Res. Commun. 238: 21-25, 1997. [PubMed: 9299444, related citations] [Full Text]

  5. Larsen, R. D., Ernst, L. K., Nair, R. P., Lowe, J. B. Molecular cloning, sequence, and expression of a human GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferase cDNA that can form the H blood group antigen. Proc. Nat. Acad. Sci. 87: 6674-6678, 1990. [PubMed: 2118655, related citations] [Full Text]

  6. Le Pendu, J., Cartron, J. P., Lemieux, R. U., Oriol, R. The presence of at least two different H-blood-group-related beta-D-Gal alpha-2-L-fucosyltransferases in human serum and the genetics of blood group H substances. Am. J. Hum. Genet. 37: 749-760, 1985. [PubMed: 9556663, related citations]

  7. Le Pendu, J., Lemieux, R. U., Lambert, F., Dalix, A.-M., Oriol, R. Distribution of H type 1 and H type 2 antigenic determinants in human sera and saliva. Am. J. Hum. Genet. 34: 402-415, 1982. [PubMed: 6177241, related citations]

  8. Oriol, R., Danilovs, J., Hawkins, B. R. A new genetic model proposing that the Se gene is a structural gene closely linked to the H gene. Am. J. Hum. Genet. 33: 421-431, 1981. [PubMed: 7246545, related citations]

  9. 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, related citations] [Full Text]


Carol A. Bocchini - updated : 2/9/2016
Carol A. Bocchini - updated : 1/14/2016
Dawn Watkins-Chow - updated : 4/16/2002
Victor A. McKusick - updated : 2/29/2000
Creation Date:
Victor A. McKusick : 6/3/1986
carol : 12/19/2018
alopez : 05/02/2016
alopez : 5/2/2016
alopez : 3/11/2016
carol : 2/9/2016
carol : 1/15/2016
carol : 1/14/2016
mcolton : 8/14/2015
alopez : 11/12/2009
terry : 4/4/2005
carol : 3/17/2004
mgross : 4/16/2002
alopez : 2/29/2000
alopez : 5/4/1998
terry : 6/18/1996
mark : 11/13/1995
jason : 7/12/1994
warfield : 4/15/1994
mimadm : 2/19/1994
supermim : 3/16/1992
carol : 3/7/1992

* 211100

FUCOSYLTRANSFERASE 1; FUT1


Alternative titles; symbols

H ANTIGEN
Hh


HGNC Approved Gene Symbol: FUT1

Cytogenetic location: 19q13.33     Genomic coordinates (GRCh38): 19:48,748,011-48,755,358 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
19q13.33 [Bombay phenotype] 616754 Autosomal recessive 3

TEXT

Cloning and Expression

Larsen et al. (1990) cloned and sequenced a gene which they showed encodes the H blood group antigen. When expressed in COS-1 cells, the cDNA directed expression of cell surface H structures and a cognate alpha-(1,2)FT activity with properties analogous to the human H blood group alpha-(1,2)FT. The cDNA predicted a 365-amino acid polypeptide.


Gene Function

All human bloods, with exceedingly rare exceptions, carry the red cell H antigen. It is present in greatest amount on type O red cells and least on type A1B cells. The H antigen is an intermediate stage in a series of syntheses ending, in the presence of the A or B genes, in the production of the corresponding A and B antigens.

Oriol et al. (1981) suggested that Hh and Se (FUT2; 182100) are both structural genes, each coding for a 2-alpha-L-fucosyltransferase. The same group (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 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.

Le Pendu et al. (1985) concluded that there are at least 2 distinct alpha-2-L-fucosyltransferases in human serum; the enzymatic activity in H-deficient secretor serum may be the product of the Se gene and the enzymatic activity found in the H-normal nonsecretor serum could be the product of the H gene. These conclusions are consistent with the close linkage of the H and Se genes, which may have arisen by gene duplication from a common ancestral gene.


Mapping

Oriol et al. (1981) found a lod score of 12.9 at 1% recombination for linkage of Se and H.

By Southern blot analysis, Larsen et al. (1990) mapped the gene encoding the H blood group antigen to chromosome 19.

From comparison of the genetic and physical maps and linkage studies using microsatellite markers, Reguigne-Arnould et al. (1995) concluded that the tightly linked FUT1-FUT2 genes are located on 19q13.3.


Molecular Genetics

In an individual with the classic Bombay phenotype (616754), Kelly et al. (1994) identified homozygosity for a nonsense mutation in the FUT1 gene (Y316X), predicting a mutant protein missing the 50 C-terminal amino acids of the wildtype enzyme. In an individual with a para-Bombay phenotype (see 616754), they identified compound heterozygous mutations in the FUT1 gene (L164H, 211100.0002 and Q276X, 211100.0003). The mutation segregated with the phenotype in both families.

In 3 unrelated individuals with the classic Bombay phenotype, Koda et al. (1997) identified a heterozygous mutation in the FUT1 gene (L242R; 211100.0004) on one allele and complete deletion of the FUT2 gene (182100.0003) on the other.

Fernandez-Mateos et al. (1998) identified a homozygous missense mutation (H117Y; 211100.0005) in the FUT1 gene as the cause of the para-Bombay phenotype (Reunion variant) on Reunion Island.


Animal Model

Using gene targeting in embryonic stem cells, Domino et al. (2001) generated mice that were deficient in Fut1. Fut1-null mice developed normally and exhibited no gross phenotypic abnormalities. Using immunohistochemistry, the authors observed that Fut1-null mice were deficient in epididymal cell surface alpha(1,2)-fucosylated glycans expressed by wildtype mice. However, normal fertility was observed. They concluded that alpha(1,2)-fucosylated glycans play nonessential roles in blastocyst implantation or sperm function in mice.


ALLELIC VARIANTS 5 Selected Examples):

.0001   BOMBAY PHENOTYPE

FUT1, TYR316TER
SNP: rs104894686, gnomAD: rs104894686, ClinVar: RCV000012922

Kelly et al. (1994) sequenced approximately 6.5 kb of genomic DNA encompassing a wildtype FUT1 allele and the corresponding region in an allele from a patient with the Bombay phenotype (616754). The Bombay allele differed from the wildtype allele at 6 positions. Three of these single nucleotide differences were in the gene's single intervening sequence, 1 was within the coding region, and 2 were in the 3-prime untranslated region. The sequence difference in the coding region was a nonsense mutation that created a termination codon corresponding to amino acid 316 of the wildtype alpha(1,2)FT: tyr316-to-ter (Y316X). This sequence alteration predicted a mutant polypeptide that is missing the 50 C-terminal amino acids of the wildtype enzyme. The mutation was present in homozygous state. To confirm that the Y316X mutation inactivates the allele, Kelly et al. (1994) moved this DNA sequence difference and each of the others into the wildtype sequence background and tested for function by transfection into an alpha(1,2)FT-deficient mammalian host, namely, COS-1 cells. The wildtype construct encoded a substantial amount of transferase activity, whereas the Bombay construct generated no enzyme activity. By contrast, vectors containing each of the other DNA sequence differences expressed normal levels of transferase activity in transfected cells.


.0002   PARA-BOMBAY PHENOTYPE

FUT1, LEU164HIS
SNP: rs104894687, ClinVar: RCV000012923

In an individual with the para-Bombay phenotype (see 616754), Kelly et al. (1994) found compound heterozygosity for 2 mutations of the FUT1 gene: leu164-to-his (L164H) and gln276-to-ter (Q276X; 211100.0003).


.0003   PARA-BOMBAY PHENOTYPE

FUT1, GLN276TER
SNP: rs104894688, gnomAD: rs104894688, ClinVar: RCV000012924

For discussion of the gln276-to-ter (Q276X) mutation in the FUT1 gene that was found in compound heterozygous state in an individual with the para-Bombay phenotype by Kelly et al. (1994), see 211100.0002.


.0004   BOMBAY PHENOTYPE, DIGENIC

BOMBAY PHENOTYPE
FUT1, LEU242ARG
SNP: rs28934588, gnomAD: rs28934588, ClinVar: RCV000012925, RCV000735637

In 3 unrelated individuals with the classic Bombay phenotype (616754), Koda et al. (1997) identified that a 725T-G transversion in the FUT1, resulting in a leu242-to-arg (L242R) substitution, and complete deletion of the FUT2 gene (182100.0003).

By sequencing the FUT1 gene in patients from Reunion Island with the Bombay phenotype (616754), Fernandez-Mateos et al. (1998) identified homozygosity for the L242R mutation.


.0005   PARA-BOMBAY PHENOTYPE

FUT1, HIS117TYR
SNP: rs150074056, gnomAD: rs150074056, ClinVar: RCV000207394

By sequencing the FUT1 gene in patients from Reunion Island with the para-Bombay phenotype (see 616754), Fernandez-Mateos et al. (1998) identified a homozygous c.349C-T transition, resulting in a his117-to-tyr (H117Y) substitution. Family segregation and transfection experiments demonstrated that this mutation is responsible for the weak H-deficient Reunion variant.


REFERENCES

  1. Domino, S. E., Zhang, L., Gillespie, P. J., Saunders, T. L., Lowe, J. B. Deficiency of reproductive tract alpha(1,2)fucosylated glycans and normal fertility in mice with targeted deletions of the FUT1 or FUT2 alpha(1,2)fucosyltransferase locus. Molec. Cell. Biol. 21: 8336-8345, 2001. [PubMed: 11713270] [Full Text: https://doi.org/10.1128/MCB.21.24.8336-8345.2001]

  2. Fernandez-Mateos, P., Cailleau, A., Henry, S., Costache, M., Elmgren, A., Svensson, L., Larson, G., Samuelsson, B. E., Oriol, R., Mollicone, R. Point mutations and deletion responsible for the Bombay H null and the Reunion H weak blood groups. Vox Sang. 75: 37-46, 1998. [PubMed: 9745152]

  3. Kelly, R. J., Ernst, L. K., Larsen, R. D., Bryant, J. G., Robinson, J. S., Lowe, J. B. Molecular basis for H blood group deficiency in Bombay (Oh) and para-Bombay individuals. Proc. Nat. Acad. Sci. 91: 5843-5847, 1994. [PubMed: 7912436] [Full Text: https://doi.org/10.1073/pnas.91.13.5843]

  4. Koda, Y., Soejima, M., Johnson, P. H., Smart, E., Kimura, H. Missense mutation of FUT1 and deletion of FUT2 are responsible for Indian Bombay phenotype at ABO blood group system. Biochem. Biophys. Res. Commun. 238: 21-25, 1997. [PubMed: 9299444] [Full Text: https://doi.org/10.1006/bbrc.1997.7232]

  5. Larsen, R. D., Ernst, L. K., Nair, R. P., Lowe, J. B. Molecular cloning, sequence, and expression of a human GDP-L-fucose:beta-D-galactoside 2-alpha-L-fucosyltransferase cDNA that can form the H blood group antigen. Proc. Nat. Acad. Sci. 87: 6674-6678, 1990. [PubMed: 2118655] [Full Text: https://doi.org/10.1073/pnas.87.17.6674]

  6. Le Pendu, J., Cartron, J. P., Lemieux, R. U., Oriol, R. The presence of at least two different H-blood-group-related beta-D-Gal alpha-2-L-fucosyltransferases in human serum and the genetics of blood group H substances. Am. J. Hum. Genet. 37: 749-760, 1985. [PubMed: 9556663]

  7. Le Pendu, J., Lemieux, R. U., Lambert, F., Dalix, A.-M., Oriol, R. Distribution of H type 1 and H type 2 antigenic determinants in human sera and saliva. Am. J. Hum. Genet. 34: 402-415, 1982. [PubMed: 6177241]

  8. Oriol, R., Danilovs, J., Hawkins, B. R. A new genetic model proposing that the Se gene is a structural gene closely linked to the H gene. Am. J. Hum. Genet. 33: 421-431, 1981. [PubMed: 7246545]

  9. 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]


Contributors:
Carol A. Bocchini - updated : 2/9/2016
Carol A. Bocchini - updated : 1/14/2016
Dawn Watkins-Chow - updated : 4/16/2002
Victor A. McKusick - updated : 2/29/2000

Creation Date:
Victor A. McKusick : 6/3/1986

Edit History:
carol : 12/19/2018
alopez : 05/02/2016
alopez : 5/2/2016
alopez : 3/11/2016
carol : 2/9/2016
carol : 1/15/2016
carol : 1/14/2016
mcolton : 8/14/2015
alopez : 11/12/2009
terry : 4/4/2005
carol : 3/17/2004
mgross : 4/16/2002
alopez : 2/29/2000
alopez : 5/4/1998
terry : 6/18/1996
mark : 11/13/1995
jason : 7/12/1994
warfield : 4/15/1994
mimadm : 2/19/1994
supermim : 3/16/1992
carol : 3/7/1992