Murine Equivalent of the Human Histo-blood Group ABO Gene Is acis-AB Gene and Encodes a Glycosyltransferase with Both A and B Transferase Activity

We have cloned murine genomic and complementary DNA that is equivalent to the human ABO gene. The murine gene consists of at least six coding exons and spans at least 11 kilobase pairs. Exon-intron boundaries are similar to those of the human gene. Unlike human A and B genes that encode two distinct glycosyltransferases with different donor nucleotide-sugar specificities, the murine gene is a cis-AB gene that encodes an enzyme with both A and B transferase activities, and thiscis-AB gene prevails in the mouse population. Cloning of the murine AB gene may be helpful in establishing a mouse model system to assess the functionality of the ABO genes in the future. We have cloned murine genomic and complementary DNA that is equivalent to the human ABO gene. The murine gene consists of at least six coding exons and spans at least 11 kilobase pairs. Exon-intron boundaries are similar to those of the human gene. Unlike human A and B genes that encode two distinct glycosyltransferases with different donor nucleotide-sugar specificities, the murine gene is a cis-AB gene that encodes an enzyme with both A and B transferase activities, and thiscis-AB gene prevails in the mouse population. Cloning of the murine AB gene may be helpful in establishing a mouse model system to assess the functionality of the ABO genes in the future. Histo-blood group A/B antigens are clinically important antigens in blood transfusion and organ transplantation. These antigens are oligosaccharide antigens whose immunodominant structures are defined as GalNAc α1→3 (Fuc α1→2) Gal- and Gal α1→3 (Fuc α1→2) Gal- for A and B antigen, respectively. Functional alleles at the ABO locus encode enzymes that catalyze the final step of synthesis. A alleles encode for A transferase, which transfers the GalNAc residues from the UDP-GalNAc nucleotide-sugar to the galactose residue of the acceptor H substrates defined by Fuc α1→2 Gal-. B alleles encode for B transferase that transfers the galactose residue from UDP-galactose to the same H substrates. O alleles are nonfunctional, null alleles. During the past decade, we have been studying the molecular genetic basis of the histo-blood group ABO system (1Yamamoto F. Vox Sang. 2000; 78: 91-103PubMed Google Scholar). From a human gastric carcinoma cell line cDNA library, we were able to clone human A transferase cDNA (2Yamamoto F. Marken J. Tsuji T. White T. Clausen H. Hakomori S. J. Biol. Chem. 1990; 265: 1146-1151Abstract Full Text PDF PubMed Google Scholar) based on the partial amino acid sequence of the soluble form of A transferase purified from human lung (3Clausen H. White T. Takio K. Titani K. Stroud M. Holmes E. Karkov J. Thim L. Hakomori S. J. Biol. Chem. 1990; 265: 1139-1145Abstract Full Text PDF PubMed Google Scholar). Using cross-hybridization with A transferase cDNA probes, we then cloned B transferase cDNA and nonfunctional O allelic cDNA from cDNA libraries made with RNA from colon adenocarcinoma cell lines that exhibited different ABO phenotypes (4Yamamoto F. Clausen H. White T. Marken J. Hakomori S. Nature. 1990; 345: 229-233Crossref PubMed Scopus (908) Google Scholar). Possible allele-specific mutations were identified. Four amino acid substitutions were discovered between A and B transferases. O alleles were more homologous to A alleles than to B alleles. A single base deletion was found near the N terminus of the coding sequence in most of the O alleles, which caused the codon frame to shift. This resulted in a truncated protein without glycosyltransferase activity. In addition to the three major alleles (A 1The abbreviations used are: PCRpolymerase chain reactionα-S-dGTP2′-deoxyguanosine-5′-O-(1-thio-triphosphate)α-S-dCTP2′-deoxycytidine-5′-O-(1-thio-triphosphate)RACErapid amplification of cDNA ends, B, and O), we also identified mutations that modified the enzymatic activity by determination of the partial nucleotide sequences of subgroup alleles (A2, A3, Ax, and B3) (5Yamamoto F. McNeill P.D. Hakomori S. Biochem. Biophys. Res. Commun. 1992; 187: 366-374Crossref PubMed Scopus (184) Google Scholar, 6Yamamoto F. McNeill P.D. Yamamoto M. Hakomori S. Harris T. Judd W.J. Davenport R.D. Vox Sang. 1993; 64: 116-119Crossref PubMed Scopus (113) Google Scholar, 7Yamamoto F. McNeill P.D. Yamamoto M. Hakomori S. Harris T. Vox Sang. 1993; 64: 171-174Crossref PubMed Scopus (100) Google Scholar). We also elucidated the molecular mechanisms of two phenomena named cis-AB and B(A) (7Yamamoto F. McNeill P.D. Yamamoto M. Hakomori S. Harris T. Vox Sang. 1993; 64: 171-174Crossref PubMed Scopus (100) Google Scholar, 8Yamamoto F. McNeill P.D. Kominato Y. Yamamoto M. Hakomori S. Ishimoto S. Nishida S. Shima M. Fujimura Y. Vox Sang. 1993; 64: 120-123Crossref PubMed Scopus (114) Google Scholar). Although the incidence was low, another type of O allele was discovered that lacked the single base deletion but contained an amino acid substitution at the residue crucial for nucleotide-sugar recognition/binding (9Yamamoto F. McNeill P.D. Yamamoto M. Hakomori S. Bromilow I.M. Duguid J.K. Vox Sang. 1993; 64: 175-178Crossref PubMed Scopus (108) Google Scholar). Although no functional analyses have been performed to disprove polymorphism, others have reported additional alterations (10Ogasawara K. Yabe R. Uchikawa M. Saitou N. Bannai M. Nakata K. Takenaka M. Fujisawa K. Ishikawa Y. Juji T. Tokunaga K. Blood. 1996; 88: 2732-2737Crossref PubMed Google Scholar, 11Ogasawara K. Bannai M. Saitou N. Yabe R. Nakata K. Takenaka M. Fujisawa K. Uchikawa M. Ishikawa Y. Juji T. Tokunaga K. Hum. Genet. 1996; 97: 777-783Crossref PubMed Scopus (113) Google Scholar, 12Olsson M.L. Chester M.A. Transfus. Med. 1998; 8: 231-238Crossref PubMed Scopus (58) Google Scholar, 13Olsson M.L. Thuresson B. Chester M.A. Biochem. Biophys. Res. Commun. 1995; 216: 642-647Crossref PubMed Scopus (52) Google Scholar, 14Olsson M.L. Chester M.A. Vox Sang. 1996; 71: 113-117Crossref PubMed Scopus (41) Google Scholar, 15Olsson M.L. Chester M.A. Transfusion. 1996; 36: 309-313Crossref PubMed Scopus (53) Google Scholar). The nucleotide and deduced amino acid sequences of a variety of ABO alleles are posted on the Blood Group Antigen Gene Mutation Database developed by Blumenfeld and colleagues (available on the World Wide Web). polymerase chain reaction 2′-deoxyguanosine-5′-O-(1-thio-triphosphate) 2′-deoxycytidine-5′-O-(1-thio-triphosphate) rapid amplification of cDNA ends A/B antigens are not restricted to humans but are widely present in nature (16Kabat E.A. Blood Group Substances: Their Chemistry and Immunochemistry. Academic Press, Inc., New York1956Google Scholar). We therefore investigated the presence/absence of homologous sequence(s) in the genomes of other species of organisms (17Kominato Y. McNeill P.D. Yamamoto M. Russell M. Hakomori S. Yamamoto F. Biochem. Biophys. Res. Commun. 1992; 189: 154-164Crossref PubMed Scopus (50) Google Scholar). Hybridization of zoo blots, using the radiolabeled human A transferase cDNA probe, showed weak signals in chicken genomic DNA but strong signals, comparable with the signal detected in human DNA, in genomic DNA from mice and other mammals. No signals were detected in genomic DNA from lower species of organisms in the evolutionary tree. We next determined the partial nucleotide sequences of the primate ABO genes (17Kominato Y. McNeill P.D. Yamamoto M. Russell M. Hakomori S. Yamamoto F. Biochem. Biophys. Res. Commun. 1992; 189: 154-164Crossref PubMed Scopus (50) Google Scholar). The glycosyltransferases responsible for A or B phenotypes in primates were shown to conserve amino acid substitutions corresponding to codons 266 and 268 in humans. A similar study was also reported by others (18Martinko J.M. Vincek V. Klein D. Klein J. Immunogenetics. 1993; 37: 274-278Crossref PubMed Scopus (56) Google Scholar). Through comparative sequence analyses of the ABO genes from humans and apes, we and others proposed a convergent hypothesis of evolution that ABO genes arose from independent mutations after the speciation of humans and apes (19Saitou N. Yamamoto F. Mol. Biol. Evol. 1997; 14: 399-411Crossref PubMed Scopus (117) Google Scholar, 20O'Huigin C. Sato A. Klein J. Hum. Genet. 1997; 101: 141-148Crossref PubMed Scopus (31) Google Scholar). No apparent disadvantages are recognized among any of the phenotypes involving the ABO polymorphism. Hemolytic disease of newborns may be a natural selection against specific combinations of blood groups between the mother and fetus. However, serious incompatibility cases are rare with ABO, since the natural antibodies against A and B antigens are mostly IgM and do not cross the placenta. Although some anti-A, B antibodies are IgG and capable of crossing the placenta, A/B antigens are not well developed in fetuses. Therefore, little damage is done. There should be some reason for the existence of ABO polymorphism in the population. It has been speculated that the possible role of the ABO system is to provide resistance against infection (21Pittiglio D.H. Wallace M.F. Gibbs F.L. Genetics and Biochemistry of A, B, H, and Lewis Antigens. American Association of Blood Banks, Arlington, VA1986: 1-56Google Scholar). Gal (Fuc an was to be the for a a for and gastric T. S. 1993; PubMed Scopus Google Scholar). A and B the which H. not to in This may the that group O have a incidence of than in any other group (21Pittiglio D.H. Wallace M.F. Gibbs F.L. Genetics and Biochemistry of A, B, H, and Lewis Antigens. American Association of Blood Banks, Arlington, VA1986: 1-56Google Scholar). against the α1→3 Gal α1→3 were to the infection of Y. K. F.L. Nature. 1996; PubMed Scopus Google Scholar). From and antibodies have been to a role in the of type of selection based on the of may have been at the ABO locus to the of species from The that an human by from group A but not from group B or O M. Clausen H. C. PubMed Scopus Google Scholar) may assess the functionality of the ABO establishing an model is an we cloned and the murine ABO gene genomic DNA which was by the of the with genomic DNA of the of was from A cDNA and an were also from A was from and and were from was from and were from and was from and from and were from and were from and was from and were from The was from and enzymes were from New or reaction and were from from the mouse genomic DNA were using a human A transferase cDNA by the T. J. A Scholar). was by the using a and B. Biochem. PubMed Scopus Google Scholar). of were DNA was with and Hybridization was then performed to enzyme DNA from clone was with and the deletion were by the Gene 1993; PubMed Scopus Google Scholar). no were the were performed with enzyme using and of E. DNA was from and for The nucleotide sequences were determined by chain using the reaction F. S. 1992; Google Scholar). were using RNA from the carcinoma cell line from a of was and used for the S. A. PubMed Scopus Google Scholar). We the cDNA amplification by the the of cDNA was from RNA using murine and cDNA the was with H, E. DNA polymerase DNA the cDNA was was with and and then with and and were in the The nucleotide sequences of and were complementary to the sequences in the coding of the murine ABO Their sequences were as and for and respectively. were a and the DNA was using the DNA were then with from the by the sequences of the were the coding of the murine ABO gene was from a murine ABO genomic the was in the the coding of the murine ABO gene. The was in the next to the used to genomic This was then and The was the and the was of the codon of the mouse ABO gene coding The the coding sequence in the coding of the mouse ABO gene was then The human B transferase with F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google was with by the and then with was in the coding of the human ABO was in the The the human B transferase cDNA sequence of exons was then to the to the gene A murine cDNA was then by from the with the from a clone in the The of the clone was in the and of the cDNA was in the coding The in the was of the and of the human cDNA The contained the coding sequence of the mouse ABO gene DNA was by the T. J. A Scholar). The cell line from a human adenocarcinoma of was used as a of DNA The H antigens on cell and have been used in similar of A and B transferase (5Yamamoto F. McNeill P.D. Hakomori S. Biochem. Biophys. Res. Commun. 1992; 187: 366-374Crossref PubMed Scopus (184) Google Scholar, F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar, F. McNeill P.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the we used for after the were and were then in and A/B transferase activity was determined by the of from or to the acceptor as F. McNeill P.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the reaction were from by The of was determined using a were used for the analyses of A/B transferases. A and B transferase were by the of from or to Although the same reaction were the reaction was from the by than DNA was by the and used to a DNA from the murine ABO gene. The and nucleotide sequences of the used were as The DNA were purified using and to DNA with the the DNA was purified and then using an DNA of the antigens in murine was using on a and were using the by the the was using The from and of mice were in and the was with and The was then a the from human colon adenocarcinoma and from group A and O were also on the for the was with and in for to activity. the was in at The was then which were with murine murine or for at The were and then with the for with the were with for α1→3 Gal The cDNA that was cloned from D.H. D.H. J. Biol. Chem. Full Text PDF PubMed Google mouse R.D. J. R.D. S. A. PubMed Scopus Google and F. L. K. 1995; Google Scholar, F. L. K. Immunogenetics. 1995; PubMed Scopus Google Scholar). do not but the against the in J. J. Med. PubMed Scopus Google Scholar). sequence corresponding to gene was shown to be a to and mutations D.H. D.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, R.D. R.D. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar). A/B the galactose with the without ABO genes and genes at both the nucleotide and deduced amino acid sequence F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar). cDNA also exhibited sequence S. A. 1996; PubMed Scopus Google Scholar). Therefore, genes are to have from the same gene and the ABO gene of murine genomic DNA showed different murine cDNA and human A transferase cDNA were used (17Kominato Y. McNeill P.D. Yamamoto M. Russell M. Hakomori S. Yamamoto F. Biochem. Biophys. Res. Commun. 1992; 189: 154-164Crossref PubMed Scopus (50) Google Scholar, R.D. J. R.D. S. A. PubMed Scopus Google Scholar). the ABO gene equivalent was to in the mouse (17Kominato Y. McNeill P.D. Yamamoto M. Russell M. Hakomori S. Yamamoto F. Biochem. Biophys. Res. Commun. 1992; 189: 154-164Crossref PubMed Scopus (50) Google Scholar). from of the murine ABO gene that mice do an ABO gene We cloned the genomic DNA sequence most of the murine ABO gene. from a murine genomic DNA library, we a of independent that with the human A transferase cDNA A showed that two named and contained the coding sequence in the coding the clone contained the sequence clone was used for the nucleotide sequence The clone the sequence was used to a ABO gene as well as a murine gene We the in the clone kilobase with more than of the coding sequence was contained in the The boundaries were determined and are shown in A and B, two other the sequence the amino acid residues has not been identified. There are six coding exons in A and in B. kilobase and base of the acceptor of coding in A, was a sequence and a respectively. These sequences may be of the coding since are found in the cDNA the sequence in B the of the sequence the sequence in the In that the acceptor of to which the of We determined the nucleotide sequence contained in the which kilobase of sequence of the acceptor of in A. No sequence corresponding to the was Therefore, the of the murine ABO genes The sequence corresponding to human coding exons and was found in in the mouse gene. However, the of amino acid residues amino was than that of human exons and amino are since may be an that two exons with an in The sequence in the clone and the cDNA sequence have been in the DNA of and The nucleotide and deduced amino acid sequences in the coding of the murine cDNA were with those of human allele in by the Gene PubMed Scopus Google Scholar) and the J. J. 1990; PubMed Scopus Google Scholar) using the are shown in was in the coding sequence in the two coding The of nucleotide and amino acid residues in the two coding exons were and between the two respectively. The amino acid sequence of the murine gene was also with the amino acid sequences of human A and B mouse and are shown in A. The of the amino acid residues of the coding sequences in the two coding exons are of between the mouse ABO and genes and of between the mouse ABO gene and the gene. the amino acid sequences of the important for the recognition/binding of The is shown in C. The cloned mouse gene was to the human ABO gene. It was also to the gene than the murine gene. We the mouse ABO gene sequence encode a functional We a in an A DNA coding sequence in the coding of the mouse genomic sequence was of the human cDNA sequence of exons in the human B transferase F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar). DNA from the was the of both A and B transferase activity was may be mutations in the as in human O alleles, we a mouse cDNA The sequence of the in the coding of the mouse gene in the was by the cDNA sequence from the This a mouse cDNA the coding from the enzymatic of the are also shown in A and B transferase were detected in the cell on we that the murine gene is an AB gene that encodes a protein capable of both UDP-GalNAc and UDP-galactose donor substrates to A and B enzymatic of from with was performed using A and B transferase and F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google were used as nonfunctional F. McNeill P.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) was used as a A and B transferase activity was determined by the of from radiolabeled to the acceptor The the in after the without from the with in the The activity of the was and is shown in the in a DNA was performed using A and B transferase and F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google were used as nonfunctional F. McNeill P.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) was used as a A and B transferase activity was determined by the of from radiolabeled to the acceptor The the in after the without from the with in the The activity of the was and is shown in the We have determined the partial nucleotide sequences of the coding in the coding of the murine ABO gene using genomic DNA from species and of The are in were and M. M. M. and M. and M. for M. others were of M. The identified nucleotide some of which resulted in amino acid However, were found at the that between the human A and B transferases. both A and B transferase were also detected in the from those of mice that exhibited amino acid Therefore, are no mutations that the donor nucleotide-sugar in the and of the gene in at least those of mice and amino acid substitutions in mouse species and nucleotide and the deduced amino acid sequences of the murine of the human ABO gene were among of mouse species and The nucleotide and the deduced amino acid sequences in the between nucleotide and in The nucleotide sequence substitutions are shown in and the amino acid substitutions are shown in A and B transferase activity was using from and the of activity and not respectively. In enzymatic A transferase activity of of protein for the human gastric carcinoma cell line cell and B transferase activity of for the human gastric carcinoma cell line cell were detected among different of in a The nucleotide and the deduced amino acid sequences of the murine of the human ABO gene were among of mouse species and The nucleotide and the deduced amino acid sequences in the between nucleotide and in The nucleotide sequence substitutions are shown in and the amino acid substitutions are shown in A and B transferase activity was using from and the of activity and not respectively. In enzymatic A transferase activity of of protein for the human gastric carcinoma cell line cell and B transferase activity of for the human gastric carcinoma cell line cell were detected among different of We have shown that the mouse equivalent of the human ABO gene encodes a protein capable of both GalNAc and galactose in using from with the of the murine gene. We have also shown the of A and B transferase activity in the murine by of in of However, the of the protein not the of A and B since the enzymatic the substrates and reaction Therefore, we next the of A and B mice were We the of murine blood using murine against A and B antigens the used for the ABO blood group of human blood No was not we A and B transferase activity in the we next performed the using of the murine No of the human blood cell was the of murine with the group A resulted in some not These that A and B antigens are not in at We therefore the of antigens using the more of shown in both A and B antigens were detected in the murine was with A antigens than with B This may be to the of UDP-galactose from the between B transferase and for the same donor The of A and B antigens may be by the for the same acceptor between and by the is in murine is that the has for the acceptor substrates than the that H We have cloned murine genomic DNA most of the coding sequence that was equivalent to the human ABO gene. The sequence the amino acid residues and the sequence to be In antigens are widely on a variety of cell in on the ABO of the These and on and to be more restricted in lower R. J. R. Vox Sang. PubMed Scopus Google Scholar, R. R. 1992; Google Scholar). the of A/B antigens between humans and of the murine gene be Functional of the murine gene has shown that the cloned murine gene is an AB gene and encodes an enzyme with both A and B transferase activity. In of the human ABO we determined the molecular of two phenomena F. McNeill P.D. Kominato Y. Yamamoto M. Hakomori S. Ishimoto S. Nishida S. Shima M. Fujimura Y. Vox Sang. 1993; 64: 120-123Crossref PubMed Scopus (114) Google Scholar) and B(A) (7Yamamoto F. McNeill P.D. Yamamoto M. Hakomori S. Harris T. Vox Sang. 1993; 64: 171-174Crossref PubMed Scopus (100) Google Scholar). cis-AB alleles encode a protein with strong A and weak B transferase B(A) alleles encode a protein with strong B and weak A transferase activity. A was found in alleles at of the amino acid substitutions that human A transferase from B transferase The cis-AB alleles were as the B(A) alleles were as in those substitution DNA of transferase and in we showed that amino acid substitutions in and activity of the enzyme F. Hakomori S. J. Biol. Chem. 1990; 265: Full Text PDF PubMed Google Scholar, F. McNeill P.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). shown in B, the amino acid residues at codons and of the murine which to human codons 266 and 268 and of amino acid substitutions between A and B were and The residue is to that of human B transferase, but the residue is than the residue of human B Therefore, the mouse enzyme is to a for donor nucleotide-sugar is more than the in may for the of not the galactose of UDP-galactose but also the GalNAc of which may for the transferase activity of the murine and the same amino acid residues as those of the murine ABO gene at codons and However, the codon in the is than in the murine AB gene. This in is than may able to catalyze the of GalNAc residues and not galactose the and role of ABO polymorphism the cloned murine AB gene be in the of mice at the ABO of group A and B mice may also be possible by in the genes after the of the enzymes that A or B transferase activity is may be a to the of A and B These may the of the gene M. T. C. 1996; PubMed Scopus Google Scholar) or the of the gene strong C. L. J. PubMed Scopus Google Scholar) to or the of the These mice with different ABO phenotypes in the same genetic may the functionality of the ABO system in the future. We N. for the and S. for the We are also to of for of

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