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T/Tn Blood Group System
The T/Tn system is so far not officially recognized as a blood group system by the International Society for Blood Transfusion (ISBT). It is included here because both T and Tn are potential erythrocyte antigens, and the molecular basis for their origin has been elucidated and a number of alleles of C1GALT1C1 gene, identified.
The T (or TF, Thomsen-Friedenreich) antigen is defined by a mucin disaccharide that is O-linked to proteins: Gal-beta1,3-GalNAc-alpha1,O-Ser/Thr. The Tn (T negative) antigen is GalNAc-alpha1,O-Ser/Thr. Thus, beta1,3-galactosylation of Tn generates the T epitope.
Usually, the T disaccharide gets further elongated and branched by actions of various glycosyltransferases such as sialyltransferases and N-acetylglucosaminyltransferases. Thus,the Tn and T antigens are precursors of many O-glycans.
Neither the T nor the Tn antigen is normally displayed on cells. However, under certain conditions, such as malignancies or viral infections, these antigens can get exposed. It is believed that neuraminidases released by microorganisms such as viruses remove sialic acid from O-mucin glycans, exposing the T antigen. The mechanism by which the T antigen appears on malignant cells is, however, unclear.
Like the T-antigen, the Tn antigen is usually 'hidden' in normal tissues because of the action of beta1,3-galactosyltransferase that elongates the Tn monosaccharide to the T disaccharide. Several different molecular mechanisms may be responsible for origin (exposure) of the Tn antigen. In most cases, the enzyme UDP-Gal:GalNAc-beta1,3-Gal transferase (core 1 beta3-GalT or T-synthase (more commonly used name)) that transfers galactose to GalNAc-alpha1,O-Ser/Thr, in a beta1,3 linkage, is absent, silenced or inactive. Usually this occurs as a result of somatic mutations at the pluripotent hematopoietic stem cell level. In addition, the function of T-synthase is dependent on the expression of a specific molecular chaperone, named Cosmc, required for its proper folding. Inactivation of this chaperone by DNA changes may interfere with the action of T-synthase. In many cases a portion of the exposed GalNAc, that constitutes the Tn antigen, becomes sialylated giving rise to the sialyl-Tn antigen (STn). Often, only a portion of total cell populations show the presence of Tn and/or STn antigens.
The Tn antigen, or O-linked alpha GalNAc is synthesized by a family of N-GalNAc transferases (GalNAcT) that transfer GalNAc to Ser of Thr of proteins, in an alpha linkage. This is the first step in the biosynthesis of many O-glycans.Twenty four unique GalNAcT genes occur in the human genome. Usually,they are tissue-specific and favor specific substrates.
The gene (C1GALT1) for T-synthase has been cloned (Ju et al. J. Biol. Chem. 2002, 277:178). It resides on chromosome 7p14-p13. C1GALT1 shares minimal homology with conserved sequences of other galactosyltransferases.It is a single gene, but shares homolgy with 4 pseudogenes. Mutations in C1GALT1 could result in the Tn antigen by inactivating or silencing T-synthase. In fact, gene-targeted mice lacking core 1 beta3-GalT expressed Tn antigen on hematopoietic, epithelial and endothelial cells (Xia et al., J. Cell. Bio. 2004, 164:451). In addition, the expression of the enzyme is dependent on another gene, C1GALT1C1, that encodes a chaperone protein - Cosmc (core 1 beta3-GalT-specific molecular chaperone) - required for its folding and activity.Mutations in this gene may also inactivate T-synthase and result in Tn antigen.
Cosmc or C1GALT1C1 was cloned by Ju and Cummings (PNAS, USA, 2002, 99:16613). It resides on chromosome Xq24 and is a single exon gene. C1GALT1C1 shares 26% sequence homology with C1GALT1 and was cloned previously as C1GALT2 by Kudo et al. who, interestingly, also showed that it has T-synthase activity.
Function of proteins
C1GALT1 gene encodes the T-synthase or core 1 synthase or glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 enzyme. C1GALT1C1 or Cosmc, also referred to as C1GALT2, is a chaperone for C1GALT1.
Both C1GALT1 and C1GALT1C1 are ubiquitously expressed.
So far, the Tn antigen is documented as being acquired due to somatic mutations.
The Tn antigen becomes exposed in idiopathic Tn syndrome (permanent mixed-field polyagglutinability), or in certain malignancies and autoimmune disorders. In case of the idiopathic Tn syndrome, the antigen may become exposed on blood cells of all lineages.It was observed in case of erythrocytes that only a portion of cells may be affected. Individuals with this rare disorder appear healthy, although they may have leukopenia, thromobocytopenia and hemolytic anemia, depending on the stage of the hematopoietic precursor cell where the mutation had occurred.
Both T and Tn antigens are markers for certain malignancies. Thus, the Tn and STn antigens show a high expression levels in human cancers and cancer cultured cells, reaching close to 90% in some cancers.The expression of T and Tn antigens, in particular the T antigen, may promote interactions with galectins mediating adhesive properties of cancer cells (Khaldoyanidi et al. J Biol Chem 2003 278 4127).Also expression of Tnand STn is often observed on IgA1 isolated from kidneys of patients with IG-A nephropathy. Recently,attempts are ongoing to generate Tn-antigen-based vaccines. It was noted that a cluster of consecutive alphaGalNAcs optimizes immunogenicity of the antigen. Slovin et al. J Clin Oncol 2003 21 4292-4298)
(An excellent and in depth review of the sections of this Introductionn and in particular of the above section, including a complete list of references can be found in the article "The Tn antigen - Structural Simplicity and Biological Complexity" by JuJ. Otto VI and Cummings RD. Angewandte Chemie Int 2011 90 1770-1791.
So far, alleles have been documented for the C1GALT1C1 gene. Changes are documented in DNA of bblood cells as well as the DNA or RNA exctracted from cancerous tissues and cell lines. In the allele listings, the C1GALT1C1 sequence with GenBank ID AY159319 is taken as the reference sequence with position 1 referring to the A of the ATG start codon (nt.257 in ref. sequence).
Other database IDs and links
An excellent and in depth review,including a complete list of references can be found in the article ?The Tn antigen ? Structural Simplicity and Biological Complexity? by Ju J, Otto VI and Cummings RD. Angewandte Chemie Int. 2011 90 1770-1791.
New PubMed entries with the terms T/Tn and blood from the last 30 days.
NCBI Book Sections with the terms T/Tn and blood.
Also see Other carbohydrate antigens
Olga O. Blumenfeld
Dept. of Biochemistry
Albert Einstein College of Medicine
Contributors for specific alleles are listed with the alleles.
Updated 2013-06-04 14:49:43.870