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TNNT2  -  troponin T type 2 (cardiac)

Homo sapiens

Synonyms: CMD1D, CMH2, CMPD2, Cardiac muscle troponin T, LVNC6, ...
 
 
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Disease relevance of TNNT2

  • Mutations of the gene (TNNT2) encoding the thin-filament contractile protein cardiac troponin T are responsible for 15% of all cases of familial hypertrophic cardiomyopathy, the leading cause of sudden death in young athletes [1].
  • OBJECTIVES: We performed genetic investigations of cardiac troponin T (TNNT2) and troponin C (TNNC1) in 235 consecutive patients with idiopathic dilated cardiomyopathy (DCM) to evaluate prevalence of mutations and associated disease expression in affected families [2].
  • Mutations in the human cardiac troponin T gene (TNNT2) are associated with familial hypertrophic cardiomyopathy (FHC) linked to chromosome 1q3 (CMH2) [3].
  • TNNT2 R278C was present in a woman with severe HC, but a sister and a daughter were mutation carriers and did not have hypertrophy [4].
  • BACKGROUND: Mutations in the cardiac beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC) [4].
 

Psychiatry related information on TNNT2

  • Certainly, cTnT measurement can be incorporated into a clinical decision-making strategy to assign patients to investigation and management pathways [5].
 

High impact information on TNNT2

  • TNNT2 mutations can also lead to dilated cardiomyopathy, a leading cause of heart failure [1].
  • CONCLUSION: In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy [6].
  • CONTEXT: Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing prognosis in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) [6].
  • RESULTS--Sensitivity of the rapid cTnT assay increased from 33% within 2 hours from the onset of chest pain to 86% after 8 hours (P < .001); specificity ranged from 86% to 100% during the same time intervals [7].
  • PATIENTS--A cohort of 100 patients admitted for evaluation of chest pain who had sufficient blood samples at presentation for measurement of creatine kinase, creatine kinase MB fraction, and rapid cTnT as well as adequate clinical data to establish the diagnosis of MI [7].
 

Chemical compound and disease context of TNNT2

  • In contrast, a missense mutation R94L in the vicinity of the strong tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM) resulted in an increase in the Ca(2+) sensitivity of force generation, as in the case of the other HCM-causing mutations in cTnT reported previously [8].
  • Biochemical markers, including total creatine kinase (total CK), creatine kinase-MB (CK-MB), the MB isoforms, and myoglobin, as well as the troponins--cardiac troponin T (cTnT) and cardiac troponin I (cTnI)--are all used for assessment of the suspected acute myocardial infarction (AMI) patient [9].
  • Addition of heparin ( approximately 100 IU/mL) to serial samples from nine acute myocardial infarction patients produced mean cTnT losses of 33% at 1-12 h after onset of chest pain, 17% at 13-48 h, and 7% after 48 h [10].
  • This study compared troponin I (cTnI) to troponin T (cTnT) in a population admitted to General Medicine Divisions in whom acute myocardial infarction (AMI) was suspected; 98 consecutive patients were included [11].
  • CONCLUSIONS: We found no clinically significant cardiac toxicity from the use of intravenous terbutaline for severe asthma as measured by serum cTnT elevations [12].
 

Biological context of TNNT2

  • Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy [13].
  • We characterized the genomic structure of 15 TNNT2 exons spliced into the adult isoform [3].
  • The disease expression associated with TNNC1 and TNNT2 mutations was severe with complete penetrance [2].
  • Three polymorphic short tandem repeat elements (D1S477, D1S2622, and D1S1723), useful for FHC pedigree analyses at CMH2, were shown to be physically tightly linked to TNNT2 [3].
  • Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy [4].
 

Anatomical context of TNNT2

  • Hybridization of the cloned cDNAs to genomic DNA identifies a single-copy gene, and using somatic cell hybrid analysis, we have mapped the corresponding gene locus (designated TNNT2) to the long arm of chromosome 1 (1cen-qter) [14].
  • We have previously cloned the first human cardiac troponin T (cTnT) cDNA and showed the differential expression of cTnT in cardiac and skeletal muscle during ontogenic development [15].
  • In this work we located the human cTnT gene by means of fluorescent in situ hybridization to 1q32 and, by sequencing thirteen cDNAs isolated from a human fetal heart cDNA library, identified three new isoforms resulting from specific combinations of three variable regions in human cTnT cDNA [15].
  • The average soluble cTnT and cTnI pools in right atrial appendages of 11 patients with right atrial and right ventricular pressures within reference values were comparable and were approximately 8% of total myocardial troponin content [16].
  • However, the studies on cardiac troponin T (cTnT) which is more sensitive and specific to myocardium after stroke are relatively scarce [17].
 

Associations of TNNT2 with chemical compounds

 

Physical interactions of TNNT2

  • This study was initiated with exons 9 and 11 of TNNT2 because of their crucial role in the binding ability of cardiac troponin T to alpha-tropomyosin, and continued with analyses in other regions of the gene [23].
 

Enzymatic interactions of TNNT2

  • Together with the observations that cTnI is a good substrate for cGK I and is effectively phosphorylated in the presence of cTnT in vitro, these findings suggest that TnT functions as an anchoring protein for cGK I and that cGK I may participate in the regulation of muscle contraction through phosphorylation of TnI [24].
 

Regulatory relationships of TNNT2

  • Pretreatment of the heparin plasma samples either with heparinase or protamine cannot completely reverse the heparin-induced decrease in cTnT and cTnI levels and therefore addition of these reagents to the commercial test systems could not significantly improve the performance of the assay [25].
 

Other interactions of TNNT2

  • In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04) [26].
  • The reverse-transcribed cDNAs were amplified by PCR using oligonucleotide primers specific for cTnT, sTnT, and cTnI sequences (GenBank accession numbers X74819, m19308, and X54163, respectively) [27].
  • On admission serum myoglobin, and cardiac troponin T (cTnT) were measured [28].
  • These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM [29].
  • BACKGROUND: Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-tropomyosin (TPM1) [30].
 

Analytical, diagnostic and therapeutic context of TNNT2

References

  1. Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. Sehnert, A.J., Huq, A., Weinstein, B.M., Walker, C., Fishman, M., Stainier, D.Y. Nat. Genet. (2002) [Pubmed]
  2. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. Mogensen, J., Murphy, R.T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P.M., McKenna, W.J. J. Am. Coll. Cardiol. (2004) [Pubmed]
  3. A rapid protocol for cardiac troponin T gene mutation detection in familial hypertrophic cardiomyopathy. Gerull, B., Osterziel, K.J., Witt, C., Dietz, R., Thierfelder, L. Hum. Mutat. (1998) [Pubmed]
  4. Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients. García-Castro, M., Reguero, J.R., Batalla, A., Díaz-Molina, B., González, P., Alvarez, V., Cortina, A., Cubero, G.I., Coto, E. Clin. Chem. (2003) [Pubmed]
  5. Troponin T or troponin I or CK-MB (or none?). Collinson, P.O. Eur. Heart J. (1998) [Pubmed]
  6. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. Morrow, D.A., Cannon, C.P., Rifai, N., Frey, M.J., Vicari, R., Lakkis, N., Robertson, D.H., Hille, D.A., DeLucca, P.T., DiBattiste, P.M., Demopoulos, L.A., Weintraub, W.S., Braunwald, E. JAMA (2001) [Pubmed]
  7. Evaluation of a rapid bedside assay for detection of serum cardiac troponin T. Antman, E.M., Grudzien, C., Sacks, D.B. JAMA (1995) [Pubmed]
  8. Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca2+ desensitization. Lu, Q.W., Morimoto, S., Harada, K., Du, C.K., Takahashi-Yanaga, F., Miwa, Y., Sasaguri, T., Ohtsuki, I. J. Mol. Cell. Cardiol. (2003) [Pubmed]
  9. Cardiac markers in the assessment of acute coronary syndromes. Christenson, R.H., Newby, L.K., Ohman, E.M. Maryland medical journal (Baltimore, Md. : 1985) (1997) [Pubmed]
  10. Troponin T and I assays show decreased concentrations in heparin plasma compared with serum: lower recoveries in early than in late phases of myocardial injury. Gerhardt, W., Nordin, G., Herbert, A.K., Burzell, B.L., Isaksson, A., Gustavsson, E., Haglund, S., Müller-Bardorff, M., Katus, H.A. Clin. Chem. (2000) [Pubmed]
  11. Comparative study of cardiac troponin I and T measurements in a routine extra-cardiological clinical setting. Pagani, F., Bonetti, G., Panteghini, M. J. Clin. Lab. Anal. (2001) [Pubmed]
  12. Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: a prospective assessment. Chiang, V.W., Burns, J.P., Rifai, N., Lipshultz, S.E., Adams, M.J., Weiner, D.L. J. Pediatr. (2000) [Pubmed]
  13. Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy. Forissier, J.F., Carrier, L., Farza, H., Bonne, G., Bercovici, J., Richard, P., Hainque, B., Townsend, P.J., Yacoub, M.H., Fauré, S., Dubourg, O., Millaire, A., Hagège, A.A., Desnos, M., Komajda, M., Schwartz, K. Circulation (1996) [Pubmed]
  14. Human cardiac troponin T: identification of fetal isoforms and assignment of the TNNT2 locus to chromosome 1q. Townsend, P.J., Farza, H., MacGeoch, C., Spurr, N.K., Wade, R., Gahlmann, R., Yacoub, M.H., Barton, P.J. Genomics (1994) [Pubmed]
  15. Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart. Mesnard, L., Logeart, D., Taviaux, S., Diriong, S., Mercadier, J.J., Samson, F. Circ. Res. (1995) [Pubmed]
  16. Different intracellular compartmentations of cardiac troponins and myosin heavy chains: a causal connection to their different early release after myocardial damage. Bleier, J., Vorderwinkler, K.P., Falkensammer, J., Mair, P., Dapunt, O., Puschendorf, B., Mair, J. Clin. Chem. (1998) [Pubmed]
  17. Serum cardiac troponin T levels as an indicator of myocardial injury in ischemic and hemorrhagic stroke patients. Apak, I., Iltumur, K., Tamam, Y., Kaya, N. Tohoku J. Exp. Med. (2005) [Pubmed]
  18. Plasma or serum samples: measurements of cardiac troponin T and of other analytes compared. Dominici, R., Infusino, I., Valente, C., Moraschinelli, I., Franzini, C. Clin. Chem. Lab. Med. (2004) [Pubmed]
  19. Myoglobin, creatine kinase MB isoforms and creatine kinase MB mass in early diagnosis of myocardial infarction in patients with acute chest pain. Penttilä, K., Koukkunen, H., Halinen, M., Rantanen, T., Pyörälä, K., Punnonen, K., Penttilä, I. Clin. Biochem. (2002) [Pubmed]
  20. Specificity of cardiac troponins I and T in renal disease. Willging, S., Keller, F., Steinbach, G. Clin. Chem. Lab. Med. (1998) [Pubmed]
  21. Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy. Ho, C.Y., Lever, H.M., DeSanctis, R., Farver, C.F., Seidman, J.G., Seidman, C.E. Circulation (2000) [Pubmed]
  22. Cardiac troponin T isoforms affect the Ca(2+) sensitivity of force development in the presence of slow skeletal troponin I: insights into the role of troponin T isoforms in the fetal heart. Gomes, A.V., Venkatraman, G., Davis, J.P., Tikunova, S.B., Engel, P., Solaro, R.J., Potter, J.D. J. Biol. Chem. (2004) [Pubmed]
  23. Hypertrophic cardiomyopathy--molecular genetic analysis of exons 9 and 11 of the TNNT2 gene in Czech patients. Capek, P., Skvor, J. Methods of information in medicine. (2006) [Pubmed]
  24. A novel interaction of cGMP-dependent protein kinase I with troponin T. Yuasa, K., Michibata, H., Omori, K., Yanaka, N. J. Biol. Chem. (1999) [Pubmed]
  25. Interaction between heparin and cardiac troponin T and troponin I from patients after coronary bypass surgery. Speth, M., Seibold, K., Katz, N. Clin. Biochem. (2002) [Pubmed]
  26. Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Villard, E., Duboscq-Bidot, L., Charron, P., Benaiche, A., Conraads, V., Sylvius, N., Komajda, M. Eur. Heart J. (2005) [Pubmed]
  27. RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle. Ricchiuti, V., Apple, F.S. Clin. Chem. (1999) [Pubmed]
  28. Myoglobin stratifies short-term risk in acute major pulmonary embolism. Pruszczyk, P., Bochowicz, A., Kostrubiec, M., Torbicki, A., Szulc, M., Gurba, H., Kuczynska, K., Berent, H. Clin. Chim. Acta (2003) [Pubmed]
  29. Mutations profile in Chinese patients with hypertrophic cardiomyopathy. Song, L., Zou, Y., Wang, J., Wang, Z., Zhen, Y., Lou, K., Zhang, Q., Wang, X., Wang, H., Li, J., Hui, R. Clin. Chim. Acta (2005) [Pubmed]
  30. Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Van Driest, S.L., Ackerman, M.J., Ommen, S.R., Shakur, R., Will, M.L., Nishimura, R.A., Tajik, A.J., Gersh, B.J. Circulation (2002) [Pubmed]
  31. A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy. Girolami, F., Olivotto, I., Passerini, I., Zachara, E., Nistri, S., Re, F., Fantini, S., Baldini, K., Torricelli, F., Cecchi, F. Journal of cardiovascular medicine (Hagerstown, Md.) (2006) [Pubmed]
  32. Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure. Potapov, E.V., Ivanitskaia, E.A., Loebe, M., Möckel, M., Müller, C., Sodian, R., Meyer, R., Hetzer, R. Transplantation (2001) [Pubmed]
  33. Molecular cloning of human cardiac troponin T isoforms: expression in developing and failing heart. Townsend, P.J., Barton, P.J., Yacoub, M.H., Farza, H. J. Mol. Cell. Cardiol. (1995) [Pubmed]
  34. Monitoring of impending myocardial damage after pleuropneumonectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma using biochemical markers. Klaase, J.M., Swaanenburg, J.C., Schouwink, H., Sosef, M.N., Bonfrer, J.M., Zoetmulder, F.A., Rutgers, E.J., Baas, P. Photochem. Photobiol. (2000) [Pubmed]
 
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