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TNNI3  -  troponin I type 3 (cardiac)

Homo sapiens

 
 
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Disease relevance of TNNI3

 

Psychiatry related information on TNNI3

  • OBJECTIVES: This study was designed to evaluate B-type natriuretic peptide (BNP) for risk assessment and clinical decision making over a range of cut points, alone and with cardiac troponin I (cTnI), in patients with non-ST-elevation acute coronary syndromes (ACS) [6].
 

High impact information on TNNI3

  • Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients [7].
  • 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 [8].
  • Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the striated muscle TnI isoforms, we confirmed that the adult human heart expresses only cTnI [9].
  • Phosphorylation of the cardiac troponin I (cTnI)-specific NH2-terminus decreases myofilament sensitivity to calcium, while phosphorylation of other cTnI sites decreases maximal myofibrillar ATPase activity [9].
  • CONCLUSIONS: These data indicate that cTnI is an important prognostic variable in patients with unstable angina [10].
 

Chemical compound and disease context of TNNI3

  • The changing heparin effects were seen for both cTnT and cTnI during time courses of individual patients with myocardial infarction [11].
  • METHODS: We studied 74 patients with chest pain at rest, electrocardiographic evidence of myocardial ischemia, and normal (<6.7 ng/mL) values of creatine kinase-MB. cTnT was measured with a commercial assay (cutoff level 0.1 ng/mL) and cTnI with a preliminary research application (cutoff level 3.1 ng/mL) [12].
  • RESULTS: The area under the receiver operator characteristic (ROC) curve for the cTnT as predictor of both overall and cardiac death was significantly greater than the area under the cTnI curve (p < 0.0001 and p = 0.01), the BNP curve (p < 0.001 and p < 0.01) or the ANP curve (p < 0.0001 and p < 0.005) [13].
  • Falsely increased results consistent with myocardial infarction by the original Dimension cTnI assay and presumably attributable to HAs were identified in 0.17% of all patients with samples submitted for cTnI analysis [14].
  • Age of over 70 years (P=0.8), Cleveland Clinic risk score (P=0.65), diabetes (P=0.26), elevated preoperative creatinine level (P=0.77), severe left ventricular dysfunction (P=0.51), the number of grafts performed (P=0.15), and change of intraoperative cTnI level relative to time course (P=0.94) did not reach statistical significance [15].
 

Biological context of TNNI3

  • Assignment of the human cardiac troponin I gene (TNNI3) to chromosome 19q13.4 by radiation hybrid mapping [16].
  • TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations [17].
  • Whether there are differential effects of PKC phosphorylation on cTnI compared to cTnI(146G) remains unknown [4].
  • Compared to cTnI controls, binary complexes with either cTnI(146G) or cTnI(43E/45E/144E) had a small effect on Ca(2+)-dependent structural opening of the N-terminal regulatory domain of cTnC as measured using Förster resonance energy transfer [4].
  • METHODS: To study the prevalence, clinical significance and functional consequences of cTnI mutations, genetic testing was performed in 120 consecutive Australian families with HCM referred to a tertiary referral centre, and results correlated with clinical phenotype [18].
 

Anatomical context of TNNI3

  • Three troponin I genes have been identified in vertebrates that encode the isoforms expressed in adult cardiac muscle (TNNI3), slow skeletal muscle (TNNI1) and fast skeletal muscle (TNNI2), respectively [19].
  • By comparing activation of tension to the open state of the N-domain of cTnC with variations in the state of cTnI, we were able to provide data supporting the hypothesis that activation of cardiac myofilaments is tightly coupled to the open state of the N-domain of cTnC [4].
  • Although the mutation G203S also showed a tendency to increase the Ca(2+) sensitivity in both myofibrils and skinned muscle fibers, no statistically significant difference compared with wild-type cTnI could be detected [5].
  • Cardiac troponin I (cTnI) is a key switch molecule in the sarcomere [18].
  • By somatic cell hybrid analysis, the locus for TNNC1 maps to human chromosome 19 and can be localised to the region p13.2-q13.2 [20].
 

Associations of TNNI3 with chemical compounds

  • Ca(2+) binding to the regulatory domain of cTnC (cNTnC) induces little structural change but sets the stage for cTnI binding [21].
  • Interestingly, the mutation is located in a putative interaction site for the nonphosphorylated N-terminal arm of cardiac troponin I (cTnI) [ Finley NL, Abbott MB, Abusamhadneh E, Gaponenko V, Dong W, Seabrook G, Howarth JW, Rana M, Solaro RJ, Cheung HC et al. (1999) EJB Lett453, 107-112] [22].
  • This interaction is almost abolished by L29Q, as observed upon protein kinase A-dependent phosphorylation of cTnI at serine 22 and serine 23 in wild-type troponin [22].
  • METHODS: Blood samples were collected with and without heparin at five hospitals. cTnT was measured by a "third generation" assay (Elecsys((R))), and cTnI was measured by a commercial immunoassay (IMMULITE((R))) [11].
  • STUDY OBJECTIVES: To compare cardiac troponin I (cTnI), cardiac troponin T (cTnT), and creatine kinase MB (CKMB mass) in patients with and without new Q wave on the ECG following coronary artery bypass graft (CABG) surgery [23].
 

Enzymatic interactions of TNNI3

  • 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].
  • A monoclonal antibody that distinguishes phospho- and dephosphorylated forms of cardiac troponin-I [25].
 

Regulatory relationships of TNNI3

 

Other interactions of TNNI3

  • When cTnT, cTnI, and cTnC were incubated individually with caspase-3, there was no detectable cleavage [27].
  • Our data further confirm close physical linkage of TNNI2 and TNNI3 on 11p15.5 [19].
  • In contrast to cTnI and cTnT, cMLC-1 and bMHC time courses were not significantly influenced by early reperfusion [28].
  • We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy [17].
  • 5. Addition of 5 mm BDM (2,3-butandione-2-monoxime), an inhibitor of actomyosin ATPase partially reverses this shift, suggesting that the mutation impairs the normal function of cTnI to fully inhibit formation of force-generating crossbridges in the absence of Ca(2)(+) [29].
 

Analytical, diagnostic and therapeutic context of TNNI3

References

  1. Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. Mogensen, J., Murphy, R.T., Kubo, T., Bahl, A., Moon, J.C., Klausen, I.C., Elliott, P.M., McKenna, W.J. J. Am. Coll. Cardiol. (2004) [Pubmed]
  2. RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle. Ricchiuti, V., Apple, F.S. Clin. Chem. (1999) [Pubmed]
  3. Effects of T142 phosphorylation and mutation R145G on the interaction of the inhibitory region of human cardiac troponin I with the C-domain of human cardiac troponin C. Lindhout, D.A., Li, M.X., Schieve, D., Sykes, B.D. Biochemistry (2002) [Pubmed]
  4. Effects of protein kinase C dependent phosphorylation and a familial hypertrophic cardiomyopathy-related mutation of cardiac troponin I on structural transition of troponin C and myofilament activation. Kobayashi, T., Dong, W.J., Burkart, E.M., Cheung, H.C., Solaro, R.J. Biochemistry (2004) [Pubmed]
  5. Functional consequences of the mutations in human cardiac troponin I gene found in familial hypertrophic cardiomyopathy. Takahashi-Yanaga, F., Morimoto, S., Harada, K., Minakami, R., Shiraishi, F., Ohta, M., Lu, Q.W., Sasaguri, T., Ohtsuki, I. J. Mol. Cell. Cardiol. (2001) [Pubmed]
  6. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. Morrow, D.A., de Lemos, J.A., Sabatine, M.S., Murphy, S.A., Demopoulos, L.A., DiBattiste, P.M., McCabe, C.H., Gibson, C.M., Cannon, C.P., Braunwald, E. J. Am. Coll. Cardiol. (2003) [Pubmed]
  7. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Kimura, A., Harada, H., Park, J.E., Nishi, H., Satoh, M., Takahashi, M., Hiroi, S., Sasaoka, T., Ohbuchi, N., Nakamura, T., Koyanagi, T., Hwang, T.H., Choo, J.A., Chung, K.S., Hasegawa, A., Nagai, R., Okazaki, O., Nakamura, H., Matsuzaki, M., Sakamoto, T., Toshima, H., Koga, Y., Imaizumi, T., Sasazuki, T. Nat. Genet. (1997) [Pubmed]
  8. 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]
  9. Troponin I phosphorylation in the normal and failing adult human heart. Bodor, G.S., Oakeley, A.E., Allen, P.D., Crimmins, D.L., Ladenson, J.H., Anderson, P.A. Circulation (1997) [Pubmed]
  10. Prognostic influence of elevated values of cardiac troponin I in patients with unstable angina. Galvani, M., Ottani, F., Ferrini, D., Ladenson, J.H., Destro, A., Baccos, D., Rusticali, F., Jaffe, A.S. Circulation (1997) [Pubmed]
  11. 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]
  12. Direct comparison of early elevations of cardiac troponin T and I in patients with clinical unstable angina. Ottani, F., Galvani, M., Ferrini, D., Ladenson, J.H., Puggioni, R., Destro, A., Baccos, D., Bosi, S., Ronchi, A., Rusticali, F., Jaffe, A.S. Am. Heart J. (1999) [Pubmed]
  13. Risk stratification using serum concentrations of cardiac troponin T in patients with end-stage renal disease on chronic maintenance dialysis. Ishii, J., Nomura, M., Okuma, T., Minagawa, T., Naruse, H., Mori, Y., Ishikawa, T., Kurokawa, H., Hirano, T., Kondo, T., Nagamura, Y., Ezaki, K., Hishida, H. Clin. Chim. Acta (2001) [Pubmed]
  14. Performance of a revised cardiac troponin method that minimizes interferences from heterophilic antibodies. Kim, W.J., Laterza, O.F., Hock, K.G., Pierson-Perry, J.F., Kaminski, D.M., Mesguich, M., Braconnier, F., Zimmermann, R., Zaninotto, M., Plebani, M., Hanna, A., Cembrowski, G.S., Scott, M.G. Clin. Chem. (2002) [Pubmed]
  15. Predictive value of perioperative cardiac troponin I for adverse outcome in coronary artery bypass surgery. Eigel, P., van Ingen, G., Wagenpfeil, S. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. (2001) [Pubmed]
  16. Assignment of the human cardiac troponin I gene (TNNI3) to chromosome 19q13.4 by radiation hybrid mapping. Mogensen, J., Kruse, T.A., Børglum, A.D. Cytogenet. Cell Genet. (1997) [Pubmed]
  17. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Murphy, R.T., Mogensen, J., Shaw, A., Kubo, T., Hughes, S., McKenna, W.J. Lancet (2004) [Pubmed]
  18. Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy: clinical, genetic and functional consequences. Doolan, A., Tebo, M., Ingles, J., Nguyen, L., Tsoutsman, T., Lam, L., Chiu, C., Chung, J., Weintraub, R.G., Semsarian, C. J. Mol. Cell. Cardiol. (2005) [Pubmed]
  19. Structural characterization of the human fast skeletal muscle troponin I gene (TNNI2). Mullen, A.J., Barton, P.J. Gene (2000) [Pubmed]
  20. The human cardiac troponin I locus: assignment to chromosome 19p13.2-19q13.2. MacGeoch, C., Barton, P.J., Vallins, W.J., Bhavsar, P., Spurr, N.K. Hum. Genet. (1991) [Pubmed]
  21. Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil. Wang, X., Li, M.X., Sykes, B.D. J. Biol. Chem. (2002) [Pubmed]
  22. Cardiac troponin C-L29Q, related to hypertrophic cardiomyopathy, hinders the transduction of the protein kinase A dependent phosphorylation signal from cardiac troponin I to C. Schmidtmann, A., Lindow, C., Villard, S., Heuser, A., Mügge, A., Gessner, R., Granier, C., Jaquet, K. FEBS J. (2005) [Pubmed]
  23. Troponin I, troponin T, or creatine kinase-MB to detect perioperative myocardial damage after coronary artery bypass surgery. Bonnefoy, E., Filley, S., Kirkorian, G., Guidollet, J., Roriz, R., Robin, J., Touboul, P. Chest (1998) [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. A monoclonal antibody that distinguishes phospho- and dephosphorylated forms of cardiac troponin-I. Cummins, B., Russell, G.J., Cummins, P. Biochem. Soc. Trans. (1991) [Pubmed]
  26. Plasma concentrations of NT-pro-BNP and cardiac troponin-I in relation to doxorubicin-induced cardiomyopathy and cardiac function in childhood malignancy. Soker, M., Kervancioglu, M. Saudi medical journal. (2005) [Pubmed]
  27. Functional consequences of caspase activation in cardiac myocytes. Communal, C., Sumandea, M., de Tombe, P., Narula, J., Solaro, R.J., Hajjar, R.J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  28. Concentration time courses of troponin and myosin subunits after acute myocardial infarction. Mair, J., Thome-Kromer, B., Wagner, I., Lechleitner, P., Dienstl, F., Puschendorf, B., Michel, G. Coron. Artery Dis. (1994) [Pubmed]
  29. Effects of the mutation R145G in human cardiac troponin I on the kinetics of the contraction-relaxation cycle in isolated cardiac myofibrils. Kruger, M., Zittrich, S., Redwood, C., Blaudeck, N., James, J., Robbins, J., Pfitzer, G., Stehle, R. J. Physiol. (Lond.) (2005) [Pubmed]
  30. Phosphorylation of human cardiac troponin I G203S and K206Q linked to familial hypertrophic cardiomyopathy affects actomyosin interaction in different ways. Deng, Y., Schmidtmann, A., Kruse, S., Filatov, V., Heilmeyer, L.M., Jaquet, K., Thieleczek, R. J. Mol. Cell. Cardiol. (2003) [Pubmed]
  31. Cardiac troponin I levels are a risk factor for mortality and multiple organ failure in noncardiac critically ill patients and have an additive effect to the APACHE II score in outcome prediction. Wu, T.T., Yuan, A., Chen, C.Y., Chen, W.J., Luh, K.T., Kuo, S.H., Lin, F.Y., Yang, P.C. Shock (2004) [Pubmed]
 
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