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Polymorphism

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Description

I Blood Group System (Ii)

Gene locus - GCNT2, IGnT

Introduction

These antigens scarcely qualify as a blood grouping system. Anti-I antiĀ­bodies are common, yet more common are anti-IH antibodies which is distinct from I or H but is presence on cells containing both. Anti-I is a cold agglutinin, so termed because its activity is enhanced at low temperature. This antibody is often seem in the serum of patients with infectious mononucleosis.

The I antigen, together with the i antigen, used to be comprised in the Ii blood group collection. However, the gene (IGnT) 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 (1) and, some mutations responsible for adult i phenotype, identified (2; 3). 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; 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 genes

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 three IGNT forms IGnTA, IGnTB and IGnTC; each is ~ 1200 bp. and encodes a protein of ~ 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 IGHTA, 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. 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.).

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.

Tissue distribution

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.

Disease association

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.

About the alleles

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.). Note that 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); because the nucleotide content of the three isoforms is not identical, for each allele, numbers referring to nucleotide positions or amino acid changes correspond to the reference sequence rather than the actual sequence of the isoforms. Nucleotide sequences of all three isoforms can be found in Yu et al.

Other database IDs and links

NCBI genesUniprot IDGenbank proteins
NP_663624 isoform A NP_001482 isoform B NP_663630 isoform C
Gene nomenclature database IDGenbank nucleic acids
NM_001491 for isoform B NM_145649 for isoform A NM_145655 for isoform C
NCBI homologenes for homologs and orthologsNCBI dbSNP for single nucleotide polymorphismsHGMD ID - at the Human Gene Mutation DatabaseOMIM ID - at Online Mendelian Inheritance in Man
600429 110800 for I system

Attribution

  • This article is licensed under the GNU Free Documentation License. Sections excerpted from Blood Group Antigen Gene Mutation Database. See: Blumenfeld OO, Patnaik SK. Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Human Mutation. 2004 Jan; 23(1):8-16. PubMed ID: 14695527

References


1. Bierhuizen et al., Genes Dev. 7: 468,1993

2. Yu et al. Blood 98:3840, 2001

3. Yu et al., Blood 101:2081, 2003; Inaba et al., Blood, 101:2870, 2003

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