|Blood Group Antigen Gene Mutation Database|
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ABO Blood Group System
The ABH antigens are not primary gene products but they are the enzymatic reaction products of enzymes called glycosyltransferases. The ABO system occurs as a result of polymorphism of complex carbohydrate structrures of glycoproteins and glycolipids expressed at the surface of erythocytes or other cells, or present in secretions, as glycan units of mucin glycoproteins. Immuno-dominant structures of A and B antigens, GalNAc alpha1->3 (Fuc alpha1->2) Gal- and Gal alpha1->3 (Fuc alpha1->2) Gal-, respectively, are synthesized by a series of reactions; the A and B transferases encoded by the functional alleles (A and B alleles) of a single gene at the ABO locus, catalyze the last step of the synthesis, while the transferase coded by the O allele is non-functional; therefore, the acceptor substrate, (H antigen: Fuc alpha1->2 Gal-) remains without a further modification and the A and B determinants are absent on surfaces of cells.
ABO gene is organized in 7 exons, and the coding sequence in the seven coding exons spans over 18kb of genomic DNA. The exons range in size from 28 to 688 bp and exons 6 and 7, the two largest exons, encode most of the coding sequence, 1062 bp in lenght. The single nucleotide deletion, found in a large number (but not all) of O alleles and responsible for the loss of the activity of the enzyme, is located in exon 6. The first of the seven nucleotide substitutions which distinguish the A and B transferases, resides in coding exon 6; exon 7, the largest of all, contains the other six nucleotide substitutions which result in four amino acid substitutions that differentiate the A and B transferases. Among those, substitutions responsible for alterations at two sites (L 266M and G268A) determine the A or B specificity of the enzyme (Yamamoto and Hakamori). This is because , as shown by crystallographic studies, those two sites reside at the active site of the enzyme and the replacement in the A enzyme, of L by M and G by A, results in an alteration of the shape of the active site pocket, so that a smaller size UDP-Gal, rather than UDP-GalNAc, becomes preferentially accomodated as a substrate. This change gives rise to the B specificity, or the B enzyme. In addition to four common alleles (A1(A101), A2(A201), B(B101) and O(O01)), numerous alleles which encode glycosyltransferases with changes in activity and/or specificity have been identified. The crystal structure of the enzyme has now been determined and this allows to model the various DNA alterations to assess their possible structural and functional consequences (Patenaude et al. Nature Structural Biology, 2002 9: 685-690).
An erythroid cell-specific regulatory element, called the "+5.8-kb site" is located in the first intron at positions +5653 to +6154 (3' from translation start site) ; it appears that DNA changes within the regulatory element specify a number of haplotypes each linked to a specific ABO allele with exceptions that may be caused by genetic recombination. (Nakajima et al. Vox Sang 2015 109 online Aug.18. Binding of the GATA-1 or 2 and RUNX1 transcription factors is required for activity of the element.The element plays a major role in the regulatory activity of the entire region. Two ABO promoters are located between nts -149 and -2 relative to the translations start site Three documented alleles of the ABO genes showing DNA changes in the promoter region, show a decreased expression of the gene and a lower serum transferase activity. (Sano et al.Blood 2012 119 5301-5310).
Function of proteins
The primary gene products of functional alleles are glycosyltransferases. The A alleles encode UDP-GalNAc: Fuc alpha1->2 Gal alpha1->3 N-acetyl-D-galactosaminyltransferase (alpha 1->3 GalNAc transferase or histo-blood group A transferase). The B alleles encode UDP-Gal: Fuc alpha1->2 Gal alpha 1->3 galactosyltransferase (alpha 1->3 galactosyltransferase or histo-blood group B transferase). O alleles encode proteins without glycosyltransferase function. Other than being the binding sites for a number of ligands, the detailed function of ABH glycan antigens remains unknown.
Gene expression is not restricted to erythroid tissues but occurs universally in most epithelial and endothelial cells. Expression of the antigens may undergo changes during development, differentiation and maturation. Aberrant expression is often observed in human pre-malignant and malignant cells. Binding of factor CBF/NF-Y to a 43 bp repeat(s) within the minisatellite sequence located in the 5'-UTR of the ABO gene, approximately -3700 bp relative to the translation initiation site, has been implicated in regulation of its transcription. (Kominato et al. J Biol Chem 1997 272: 25890-25898). Recent studies show that polymorphism among alleles in this region regarding sequence variation and/or repeat content, may influence the level of expression (Seltsam et al. Transfusion 2007, 47: 2330-2335). More generally, a relatively high level of DNA variation has been demonstrated recently in the 5'- UTR region of the ABO gene; the changes seem not to affect the ABO phenotypes and it is still not clear what effect they may have on the level of expression of the various alleles. ( Twu et al. Transfusion 2006 46 1988-1996; Yan et al. Vox Sang 2008 94 227-233; Thuresson et al. Transfusion 2008 48 493-504). Variation among alleles is also documented in the 3'region ( Thuresson et al. Transfusion 2008 48 493-504). Most recently, the presence in intron1 of a regulatory element, specific for erythroid cells only, was demonstrated (Sano et al. Blood 2012 119 5301-5310).
None; The A, B alleles are dispensable and no apparent physiological disadvantages are noted for the null phenotype O. ABO incompatible transfusion may result in death of patients. HDN (hemolytic disease of the newborn) due to ABO incompatibility is rare. A large number of studies have examined associations between ABO blood groups and a variety of diseases or conditions, but so far consistent observations have been few. Those include the association of blood group O individuals with increased incidence of ulcers and gastric carcinoma and increased susceptibility to Helicobacter pylori. Levels of von Willebrand factor, a coagulation glycoprotein, seem to be consistently about 25% lower in blood group O individuals (Jenkins and O'Donnell, Transfusion 2006 46 1836).
In cases of chimerism, when serological testing indicates in addition to the major allele, the presence of a minor allele, in an individual's blood, a recent article describes a sensitive and efficient genotyping approach to detect the relative ratios of the two alleles. The approach depends on use of allele-specific locked nucleic acid -mediated PCR clamping (Sano R et al. Blood Transfusion 2014 online February1,2014; for description of the clamping method see Braasch DA & Corey DR. Chemical Biology 2001 8 1-7)
As will become apparent in the list of alleles, subgroups of each category of ABO alleles (A, B or O) have been documented, first serologically, as they exhibited unique phenotypes under defined conditions; also by characteristic transferase activities, and more recently, at the nucleotide sequence level. The latter studies are revealing that DNA variation (single or multiple mutations,rearrangements) occur in each category, often in a recurrent fashion, i.e. in a number of alleles, identical mutations occur at one or more identical sites.It has been proposed that recurrent mutations occurred through meiotic recombination. The incidence of the occurrence of the various alleles in world populations is not known (except for selected populations, such as the Japanese, see Ogasawara K. et al.) and there seems to be a difference in frequency among different ethnic groups. In the Table below, percent allelic frequency for each allele represents the sum of all the alleles in that category.
When referring to the list of alleles, allele A101 is taken as reference.In the list of alleles, the genomic or cDNA changes are numbered according to recommendations of den Dunnen and Antonarakis (Human Mutation 2000, 15:7-12) so that "A" of the first codon is number 1. For intronic sequences described in Seltsam et al. or Roubinet et al. nucleotide positions are numbered starting from the first nucleotide of each intron. For 5'UTR reference see "details" page. Results, for the same allele, originating from different laboratories (as different regions of the allele may have been sequenced) are referred to when they are not identical; exonic mutations are similarly referred to for the origin of their documentation.
|Allele||Protein||% in USA among caucasians | blacks | orientals|
|A1||A1 transferase||22 | 12 | 18|
|A2||A2 transferase||7 | 6 | rare|
|B||B transferase||6 | 12 | 17|
|O||non-functional||65 | 70 | 65|
Among South American Indians, whereas the incidence of A1, A2 or B allele is rare, that of the O allele is 90-100%. The distribution of ABO genotypes including allele frequencies in a sample of Chinese or white European population was documented in an article by SP Yip, Blood, 95:1487, 2000.
|Compilation of ABO alleles in BGMUT. (Excel; March 2011)|
Other database IDs and links
Dr. Fumiichiro Yamamoto, Institut de Medicina Predictiva i Personalitzada del Cancer (IMPPC) 08916 Badalona, Spain. email: email@example.com
Contributors for specific alleles are listed with the alleles.
Updated 2015-11-14 20:57:53.070