The Tn syndrome (formerly called Permanent Mixed-Field Polyagglutinability) is a very rare acquired disorder affecting all hemopoietic lineages which are characterized by the expression of the Tn and the sialosyl-Tn antigens on the cell surface. The idiopathic Tn syndrome occupies a unique well-defined field of Glycosylation disorders for two reasons: first, it is up till now the only known permanent, well-defined disorder of O-glycosylation and second, the disorder is acquired and confined to a fraction only of hemopoietic cells of all lineages.
A rare form of polyagglutination with a carbohydrate-based etiology is Tn syndrome. Tn syndrome arises from a somatic mutation in HSCs. The mutation affects an X-linked gene, one that encodes a molecular chaperone (COSMC) for a key enzyme in O-glycan biosynthesis, the core 1 β-1,3-galactosyltransferase. Loss of COSMC results in failure of core 1 β3-galactosyltransferase to properly fold and therefore develop enzyme activity, resulting in truncated O-glycans at the first Monosaccharide GalNAc. GalNAc is added by a series of polypeptide GalNAc-transferases (Fig.1), thus loss of COSMC results in the incorporation of many copies of terminal GalNAc moieties, known as the Tn antigen. Tn antigen is not normally expressed on cell surfaces, thus immune tolerance does not typically develop toward the Tn antigen. In molecular terms, the Tn antigen is an N-acetyl-galactosamine linked O-glycosidically to threonine or serine residues of membrane proteins. In Tn syndrome, these antigens bind naturally occurring serum antibodies thereby leading to mild hemolytic anemia and more pronounced thrombopenia.
Fig.1 O-glycan core 1 and N-linked glycan structure. (Lee-Sundlov, et al., 2020)
It was not evident in the early days that the Tn antigen causing polyagglutinability was a Carbohydrate. Subsequently, the Tn antigen was identified as unsubstituted-linked N-acetylgalactosamine (a GalNAc). This structure is rarely found in cells from healthy blood donors since this sugar is substituted by Galactose and sialic acid to form a tetrasaccharide as shown in Fig.2. The blood cells in the Tn syndrome are, therefore, expected to carry less sialic acid if galactose can not be transferred to GalNAc as predicted based on serological and biochemical evidence. More recently, by use of well-defined monoclonal antibodies, it was found that part of the exposed Tn epitopes is substituted in an α2→6linkage with sialic acid; this epitope is designated as sialosyl-Tn. Three properties of the Tn syndrome render it quite carry less sialic acid if galactose can not be transferred to GalNAc as predicted based on serological and biochemical evidence. Three properties of the Tn syndrome render it quite intriguing: i) its acquisition (as opposed to inheritance); ii) its stability over many years; iii) its coexistence with normal blood cells. The explanation of the underlying mechanism causing this defect may lead to new scientific territories.
Fig.2 Scheme of Tn, sialosyl-Tn, and TF antigen expression of the cell surface. (Berger, et al., 1994)
The prevalence of Tn syndrome is extremely low. In summary, patients affected by idiopathic Tn syndrome generally do well except for minor signs of hemolysis or thrombocytopenia. They are usually found by alert technicians testing blood in normal blood donors or patients for an unrelated clinical problem and observing the phenomenon of polyagglutinability. Often, a thorough work-up is not deemed important since therapeutic consequences are not warranted.
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