Alternative titles; symbols
SNOMEDCT: 40387008; DO: 0080520;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq24 | Tn polyagglutination syndrome, somatic | 300622 | 3 | C1GALT1C1 | 300611 |
A number sign (#) is used with this entry because of evidence that Tn polyagglutination syndrome (TNPS) is caused by somatic mutation in the C1GALT1C1 gene (300611) on chromosome Xq24.
Polyagglutination refers to red blood cells that agglutinate upon exposure to almost all human sera, but not to autologous serum or the sera of newborns. The condition becomes apparent during blood typing and cross-matching in the laboratory (summary by Beck, 2000).
Tn polyagglutination syndrome is an acquired clonal disorder characterized by the polyagglutination of red blood cells by naturally occurring anti-Tn antibodies following exposure of the Tn antigen on the surface of erythrocytes. Only a subset of red cells express the antigen, which can also be expressed on platelets and leukocytes. This condition may occur in healthy individuals who manifest asymptomatic anemia, leukopenia, or thrombocytopenia; however, there is also an association between the Tn antigen and leukemia or myelodysplastic disorders. The Tn antigen is an incompletely glycosylated membrane glycoprotein with an exposed N-acetylgalactosamine residue. The Tn antigen results from inactivation of C1GALT1C1, which encodes a chaperone required for the correct functioning of T-synthetase (C1GALT1; 610555), an enzyme essential for the correct biosynthesis of O-glycans. Absence of active T-synthetase results in exposure of GalNAc residues, with a proportion of these residues becoming sialylated and forming a sialyl-Tn antigen (summary by Vainchenker et al., 1985 and Crew et al., 2008).
Dausset et al. (1959) reported a 65-year-old man who developed persistent hemolytic anemia after blood transfusion for anemia after an acute infection. The anemia was accompanied by thrombocytopenia and leukopenia. Laboratory studies indicated that his red cells had a tendency to autoagglutinate. Transfusions with washed red cells were well tolerated, and the patient responded well to steroid treatment. Serologic studies showed that the abnormal agglutinin (antibody) that acted on his red cells was present in all other human sera and was independent of the ABO blood group; Dausset et al. (1959) called the agglutinin anti-Tn. However, sera from newborn infants did not agglutinate the patient's cells. In addition, the patient's serum contained an antibody that was specific for his red cells, especially when the cells were treated with a proteolytic enzyme. The Tn antigen was not found on erythrocytes of 25 family members. One of the hypotheses put forth by Dausset et al. (1959) was that the persistent hemolytic anemia in this patient was directly related to the Tn antigen on the patient's cells and was due to the development of an anti-Tn antibody against the Tn antigen. The Tn antigen may either be a rare blood group antigen or an antigen revealed or modified by the causal agent of the disease.
Cartron et al. (1978) proposed that deficiency of 3-beta-D-galactosyltransferase, resulting in defective membrane synthesis, accounts for the serologic and physicochemical properties of Tn-polyagglutinable erythrocytes. Tn-polyagglutinability is an acquired condition in which there are 2 erythrocyte populations: one normal and the other with the Tn cryptantigen exposed. Anti-Tn antibodies are present in most normal human adult sera. Since leukocytes and platelets are affected as well as red cells, anemia, leukopenia and thrombocytopenia are features. Tn-polyagglutinability is sometimes associated with leukemia or is a preleukemic state.
Vainchenker et al. (1985) demonstrated that the Tn antigen is present on hematopoietic progenitors of all cell lines (erythroid, granulocytic, and megakaryocytic) of patients with Tn syndrome, indicating that the antigen is present at early stages of differentiation.
Ju and Cummings (2005) showed that Tn syndrome is associated with somatic mutations in COSMC (C1GALT1C1; 300611), a gene on the X chromosome that encodes a molecular chaperone that is required for the proper folding and hence full activity of T synthase (C1GALT1). Ju and Cummings (2005) sequenced the T synthase and COSMC genes from whole blood cells from 2 individuals with Tn syndrome and found no mutations in T synthase. However, in 1 individual they found 2 somatic mutations in the COSMC gene (300611.0002 and 300611.0003); a second individual carried a different COSMC somatic mutation (300611.0001). In vitro function expression studies indicated that the mutations caused loss of COSMC chaperone function, leading to inactivation of T synthase and expression of the Tn antigen on blood cells of all lineages.
Crew et al. (2008) identified 2 different somatic mutations in the C1GALT1C1 gene (300611.0004-300611.0005) in 2 unrelated patients with Tn syndrome. Expression of the mutations in Jurkat T lymphocytes resulted in the cells expressing the Tn antigen, indicating loss of C1GALT1C1 function. Analysis of the transcriptome of cultured normal and Tn positive erythroblasts revealed numerous differences in gene expression, including reduced transcript levels of FABP5 (605168) and PLXND1 (604282), and increased levels of AQP3 (600170). These data showed that alteration of O-glycan structures resulting from T-synthase deficiency is accompanied by altered expression of a wide variety of genes in erythroid cells.
Beck, M. L. Red blood cell polyagglutination: clinical aspects. Semin. Hemat. 37: 186-196, 2000. [PubMed: 10791887] [Full Text: https://doi.org/10.1016/s0037-1963(00)90043-x]
Cartron, J. P., Cartron, J., Andreu, G., Salmon, C., Bird, G. W. G. Selective deficiency of 3-beta-D-galactosyltransferase (T-transferase) in Tn-polyagglutinable erythrocytes. Lancet 311: 856-857, 1978. Note: Originally Volume I. [PubMed: 76801] [Full Text: https://doi.org/10.1016/s0140-6736(78)90197-6]
Crew, V. K., Singleton, B. K., Green, C., Parsons, S. F, Daniels, G., Anstee, D. J. New mutations in C1GALT1C1 in individuals with Tn positive phenotype. Brit. J. Haemat. 142: 657-667, 2008. [PubMed: 18537974] [Full Text: https://doi.org/10.1111/j.1365-2141.2008.07215.x]
Dausset, J., Moullec, J., Bernard, J. Acquired hemolytic anemia with polyagglutinability of red blood cells due to a new factor present in normal human serum (Anti-Tn). Blood 14: 1079-1093, 1959. [PubMed: 13814231]
Ju, T., Cummings, R. D. Chaperone mutation in Tn syndrome. Nature 437: 1252 only, 2005. [PubMed: 16251947] [Full Text: https://doi.org/10.1038/4371252a]
Vainchenker, W., Vinci, G., Testa, U., Henri, A., Tabilio, A., Fache, M.-P., Rochant, H., Cartron, J.-P. Presence of the Tn antigen on hematopoietic progenitors from patients with the Tn syndrome. J. Clin. Invest. 75: 541-546, 1985. [PubMed: 3973016] [Full Text: https://doi.org/10.1172/JCI111730]