|Blood Group Antigen Gene Mutation Database|
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I Blood Group System
The I antigen, together with the i antigen, used to be comprised in the Ii blood group collection. However, the gene encoding the I beta-1,6-N-acetyl glucosamine transferase (I beta-1,6-GlcNAcT, GCNT2) responsible for converting i active straight chains of carbohydrates to I-active branched chains has been cloned (Bierhuizen et al., Genes Dev. 7: 468,1993) and, some mutations responsible for adult i phenotype, identified (Yu et al. Blood 98:3840, 2001; Yu et al., Blood 101:2081, 2003; Inaba et al., Blood, 101:2870, 2003). Hence, I has been promoted to the system status, the I blood group system, which comprises only a single antigen, the I antigen.
The i and I antigens are carbohydrate structures characterized, as linear and branched repeats of N-acetyl lactosamine, Galbeta1-4GlcNAc1-3Galbeta1-4GlcNAc-R and Galbeta1-4GlcNAc1-3 (Galbeta1-4GlcNAcbeta1-6))Galbeta1-4GlcNAc-R, respectively (poly LacNAcs). These glycans reside on O- or N-linked glycans of extracellular domains of erythrocyte membrane proteins and on membrane glycosphingolipids. In analogy to the ABO, H/h or Lewis systems, the gene loci encode glycosyltransferases responsible for the synthesis of the actual epitopes. The i antigen, the precursor of I, is synthesized by the sequential action of two glycosyl transferases, beta-1,3-acetyl glucosaminyl transferase and beta-1,4 galactosyl transferase. The I antigen is a branched form of the linear i antigen, branching being initiated by a third transferase, the I beta 1,6 GlnAc T, the I branching enzyme, also known as GCNT2 or IGnT; this enzyme differs from other branching beta 1,6 glycosyl transferases (Yeh et al.). The expression of the I and i antigens reflects a reciprocal relationship that is developmentally regulated. Adult human erythrocytes (RBCs) fully express I antigens and contain only a few i antigens; the latter predominate in fetal and neonatal RBCs. After birth, the quantity of I antigens gradually increases as the level of i antigen falls, until the normal adult Ii status is reached, about 18 months of life. Most adult RBCs fully express the I antigen; however, in a small number of individuals, only very low levels of I antigen can be detected and their RBCs show high levels of the i antigen. This phenotype is called the "adult i" and is believed to result from lack of activity of the I branching transferase, product of IGNT locus. In analogy to the other carbohydrate blood group systems, in addition to erythrocyte membrane proteins and glycolipids, the i and I epitopes reside on water soluble glycoproteins of secretions, including saliva, milk, plasma, gastric juice, ovarian cyst fluid and amniotic fluid. In these tissues the expression of I,i is also developmentally regulated but is independent of the I phenotype of the erythrocytes. Thus, normal quantities of the I antigen have been observed in milk, saliva and plasma of individuals with the adult i phenotype, suggesting that different I-branching enzymes may be responsible for i-antigen synthesis in different tissues.
The locus responsible for the formation of the blood group I antigen is the IGNT gene (Bierhuizen et al.) Studies of DNA from individuals with the adult i phenotype (Yu et al.) suggested that the locus expresses, through the use of alternative promoters, three IGNT forms IGnTA, IGnTB and IGnTC (1209, 1203, 1209bp respectively) and each encodes a protein of 402 or 400 residues; the three proteins share identical carboxy terminal regions, encoded by identical exons 2 and 3, but differ within the amino terminal regions, encoded by exons 1 (~66% sequence identity). The three isoforms are differentially expressed in various human tissues. Recently, another group of investigators reported similar findings (Inaba et al.). They propose that a single IGNT gene gives rise by alternative splicing to three isoforms designated IGNT1, IGNT2 and IGNT3. Those three isofoms are equivalent to IGNTA, IGNTB and IGNTC. Whether a single gene or three distinct genes result in these transcripts and whether they are generated by alternative splicing is still not fully clear and needs further study. Recently, adaptive evolution was proposed to play a role in creating multiple variable first exons resulting in IGNT diversity (Li and Wu, PMID: 17475008). The molecular basis proposed for the expression of IGNT locus offers a new perspective for the formation and expression of I antigen in different cells, and supports the proposition for the existence of more than one I-branching enzyme (Yu et al.). Studies of IGNT in reticulocytes and lens-epithelium cells of two groups of adult i individuals, with and without congenital cataracts, showed that the IGNTC (IGNT3) form is responsible for the expression of the I antigen on RBCs and provided a molecular basis for the partial association of the adult i phenotype with congenital cataracts (Yu et al.).More recently it was shown that the activity of IGnTC resulting in branching, during erythroid differentiation, are regulated by the transcription factor CCAAT enhancer binding protein alpha(C/EBPalpha) (Twu et al. Blood2007, 110,4526-4534).
Function of proteins
Initiation of branching of poly-LacNAc glycan units on O- and/or N-linked saccharides of membrane proteins and lipids. Receptors, ligands in adhesion processes.
Erythroid cells, lymphocytes, monocytes, granulocytes, platelets, secretions, lens epithelium and other tissues. Differential expression of specific transcripts in different tissues. For example, of IGNTC in erythroid tissues and of IGNTB in lens epithelium.
Anti-I is associated with cold agglutinin hemagglutinin disease; decreased expression of I and increased expression of i antigens is observed in oncogenesis, thalassemias, sickle cell anemias and is associated with congenital cataracts in Asian populations.
The existence of a human I genetic polymorphism was first indicated by the discovery of adult individuals whose erythrocytes were I negative but i positive and who carried a cold-agglutinating anti-I antibody. The I negative phenotype, known as "adult i," is rare in world populations; it has been reported to be associated with congenital cataracts in Asians. Its molecular basis was recently elucidated in two groups of individuals; six adult i caucasian individuals with no cataracts and five adult i Taiwanese individuals with congenital cataracts (Yu et al.); also, in three adult i individuals with congenital cataracts and five individuals with common I phenotype (Inaba et al.). As noted above the processing of IGnT results in three transcripts IGnTA, IGnTB, IGnTC that differ at the amino terminus but are identical in the carboxyl terminal regions.
In the list of alleles, GenBank sequence with acc no. NM_00149 is used as reference (coding region starts at nt. 709);however, as noted above, gene transcripts occur as isoforms that share exons 2 and 3 but differ in exon 1; because the numbers of nt in the 3 isoforms differ ( the number of nucleotides in exon 1 of IGnTB is decreased by 6 (2 fewer amino acids) reference sequences for the isoforms are included and are used when the respective forms of alleles are known or AF458024 for IGnT A, AF458025 for IGnT B and AF458026 for IGnT C. When in an allele, DNA variation occurs in exon 1 it may or may not be found in all 3 isoforms; however if it occurs in exons 2 or 3, it will occur in all 3 isoforms but at correspondingly different positions.Thus, to obtain the position of the same nucleotide change, for IGntB substract 6bp from the position shown for IGntA and/or C; if shown in IGnTB, add 6nt for the corresponding position in A or C. In the Table of alleles, nucleotide changes are shown as indicated in the original publications.
Other database IDs and links
Yu Lung-Chih, Institute of Biochemical Sciences, National Taiwan University, P.O.Box 23-106, Taipei, Taiwan; tel. 886-2-2362-0261, ext. 2022; fax. 886-2-2363-5038
Marie Lin, Transfusion Medicine Laboratory, Mackay Memorial Hospital, 45 Ming-San Road, Taipei, County 251, Taiwan; tel. 886-2-2809-4661, ext. 2380; fax. 886-2-2809-4679
Contributors for specific alleles are listed with the alleles.
Updated 2011-08-09 05:15:13.540