6kn8

Structural highlights

Disease

[TNNC1_HUMAN] Defects in TNNC1 are the cause of cardiomyopathy dilated type 1Z (CMD1Z) [MIM:611879]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.^[1] Defects in TNNC1 are the cause of familial hypertrophic cardiomyopathy type 13 (CMH13) [MIM:613243]. A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.^{[2] [3] [4] [5]} [TNNT2_HUMAN] Defects in TNNT2 are the cause of familial hypertrophic cardiomyopathy type 2 (CMH2) [MIM:115195]. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.^{[6] [7] [8] [9] [10]} [:]^{[11] [12] [13] [14] [15] [16] [17] [18]} Defects in TNNT2 are the cause of cardiomyopathy dilated type 1D (CMD1D) [MIM:601494]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.^{[19] [20] [21] [22] [23]} Defects in TNNT2 are the cause of familial restrictive cardiomyopathy type 3 (RCM3) [MIM:612422]. Restrictive cardiomyopathy is a heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function.^[24] [TPM1_HUMAN] Left ventricular noncompaction;Familial isolated hypertrophic cardiomyopathy;Familial isolated dilated cardiomyopathy. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [TNNI3_HUMAN] Defects in TNNI3 are the cause of familial hypertrophic cardiomyopathy type 7 (CMH7) [MIM:613690]. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.^{[25] [26] [27] [28] [29]} Defects in TNNI3 are the cause of familial restrictive cardiomyopathy type 1 (RCM1) [MIM:115210]. RCM1 is a heart muscle disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function.^[30] Defects in TNNI3 are the cause of cardiomyopathy dilated type 2A (CMD2A) [MIM:611880]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.^[31] Defects in TNNI3 are the cause of cardiomyopathy dilated type 1FF (CMD1FF) [MIM:613286]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.

Function

[TNNC1_HUMAN] Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments. [TNNT2_HUMAN] Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. [ACTS_RABIT] Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. [TPM1_HUMAN] Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. [TNNI3_HUMAN] Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.

References

1. ↑ Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2004 Nov 16;44(10):2033-40. PMID:15542288 doi:S0735-1097(04)01700-0
2. ↑ Hoffmann B, Schmidt-Traub H, Perrot A, Osterziel KJ, Gessner R. First mutation in cardiac troponin C, L29Q, in a patient with hypertrophic cardiomyopathy. Hum Mutat. 2001 Jun;17(6):524. PMID:11385718 doi:10.1002/humu.1143
3. ↑ Schmidtmann A, Lindow C, Villard S, Heuser A, Mugge A, Gessner R, Granier C, Jaquet K. 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. FEBS J. 2005 Dec;272(23):6087-97. PMID:16302972 doi:10.1111/j.1742-4658.2005.05001.x
4. ↑ Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008 Aug;45(2):281-8. doi: 10.1016/j.yjmcc.2008.05.003. Epub , 2008 May 11. PMID:18572189 doi:10.1016/j.yjmcc.2008.05.003
5. ↑ Pinto JR, Parvatiyar MS, Jones MA, Liang J, Ackerman MJ, Potter JD. A functional and structural study of troponin C mutations related to hypertrophic cardiomyopathy. J Biol Chem. 2009 Jul 10;284(28):19090-100. doi: 10.1074/jbc.M109.007021. Epub, 2009 May 12. PMID:19439414 doi:10.1074/jbc.M109.007021
6. ↑ Gerull B, Osterziel KJ, Witt C, Dietz R, Thierfelder L. A rapid protocol for cardiac troponin T gene mutation detection in familial hypertrophic cardiomyopathy. Hum Mutat. 1998;11(2):179-82. PMID:9482583 doi:<179::AID-HUMU12>3.0.CO;2-W 10.1002/(SICI)1098-1004(1998)11:2<179::AID-HUMU12>3.0.CO;2-W
7. ↑ Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701-12. PMID:8205619
8. ↑ Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, et al.. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995 Apr 20;332(16):1058-64. PMID:7898523
9. ↑ Forissier JF, Carrier L, Farza H, Bonne G, Bercovici J, Richard P, Hainque B, Townsend PJ, Yacoub MH, Faure S, Dubourg O, Millaire A, Hagege AA, Desnos M, Komajda M, Schwartz K. Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy. Circulation. 1996 Dec 15;94(12):3069-73. PMID:8989109
10. ↑ Moolman JC, Corfield VA, Posen B, Ngumbela K, Seidman C, Brink PA, Watkins H. Sudden death due to troponin T mutations. J Am Coll Cardiol. 1997 Mar 1;29(3):549-55. PMID:9060892
11. ↑ Varnava A, Baboonian C, Davison F, de Cruz L, Elliott PM, Davies MJ, McKenna WJ. A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy. Heart. 1999 Nov;82(5):621-4. PMID:10525521
12. ↑ Nakajima-Taniguchi C, Matsui H, Fujio Y, Nagata S, Kishimoto T, Yamauchi-Takihara K. Novel missense mutation in cardiac troponin T gene found in Japanese patient with hypertrophic cardiomyopathy. J Mol Cell Cardiol. 1997 Feb;29(2):839-43. PMID:9140840 doi:S0022-2828(96)90322-3
13. ↑ Ho CY, Lever HM, DeSanctis R, Farver CF, Seidman JG, Seidman CE. Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy. Circulation. 2000 Oct 17;102(16):1950-5. PMID:11034944
14. ↑ Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. Epub 2003 Apr 21. PMID:12707239 doi:10.1161/01.CIR.0000066323.15244.54
15. ↑ Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 2003 Oct;64(4):339-49. PMID:12974739
16. ↑ Song L, Zou Y, Wang J, Wang Z, Zhen Y, Lou K, Zhang Q, Wang X, Wang H, Li J, Hui R. Mutations profile in Chinese patients with hypertrophic cardiomyopathy. Clin Chim Acta. 2005 Jan;351(1-2):209-16. PMID:15563892 doi:10.1016/j.cccn.2004.09.016
17. ↑ Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005 Oct;42(10):e59. PMID:16199542 doi:10.1136/jmg.2005.033886
18. ↑ Millat G, Bouvagnet P, Chevalier P, Sebbag L, Dulac A, Dauphin C, Jouk PS, Delrue MA, Thambo JB, Le Metayer P, Seronde MF, Faivre L, Eicher JC, Rousson R. Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. Eur J Med Genet. 2011 Nov-Dec;54(6):e570-5. doi: 10.1016/j.ejmg.2011.07.005. Epub, 2011 Aug 4. PMID:21846512 doi:10.1016/j.ejmg.2011.07.005
19. ↑ Millat G, Bouvagnet P, Chevalier P, Sebbag L, Dulac A, Dauphin C, Jouk PS, Delrue MA, Thambo JB, Le Metayer P, Seronde MF, Faivre L, Eicher JC, Rousson R. Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. Eur J Med Genet. 2011 Nov-Dec;54(6):e570-5. doi: 10.1016/j.ejmg.2011.07.005. Epub, 2011 Aug 4. PMID:21846512 doi:10.1016/j.ejmg.2011.07.005
20. ↑ Kamisago M, Sharma SD, DePalma SR, Solomon S, Sharma P, McDonough B, Smoot L, Mullen MP, Woolf PK, Wigle ED, Seidman JG, Seidman CE. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med. 2000 Dec 7;343(23):1688-96. PMID:11106718 doi:10.1056/NEJM200012073432304
21. ↑ Li D, Czernuszewicz GZ, Gonzalez O, Tapscott T, Karibe A, Durand JB, Brugada R, Hill R, Gregoritch JM, Anderson JL, Quinones M, Bachinski LL, Roberts R. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation. 2001 Oct 30;104(18):2188-93. PMID:11684629
22. ↑ Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2004 Nov 16;44(10):2033-40. PMID:15542288 doi:S0735-1097(04)01700-0
23. ↑ Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N, Komajda M. Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Eur Heart J. 2005 Apr;26(8):794-803. Epub 2005 Mar 15. PMID:15769782 doi:ehi193
24. ↑ Peddy SB, Vricella LA, Crosson JE, Oswald GL, Cohn RD, Cameron DE, Valle D, Loeys BL. Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene. Pediatrics. 2006 May;117(5):1830-3. PMID:16651346 doi:10.1542/peds.2005-2301
25. ↑ Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA, Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, Imaizumi T, Sasazuki T. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet. 1997 Aug;16(4):379-82. PMID:9241277 doi:10.1038/ng0897-379
26. ↑ Niimura H, Patton KK, McKenna WJ, Soults J, Maron BJ, Seidman JG, Seidman CE. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation. 2002 Jan 29;105(4):446-51. PMID:11815426
27. ↑ Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. Epub 2003 Apr 21. PMID:12707239 doi:10.1161/01.CIR.0000066323.15244.54
28. ↑ Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. 2003 Oct;64(4):339-49. PMID:12974739
29. ↑ Ingles J, Doolan A, Chiu C, Seidman J, Seidman C, Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. J Med Genet. 2005 Oct;42(10):e59. PMID:16199542 doi:10.1136/jmg.2005.033886
30. ↑ Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest. 2003 Jan;111(2):209-16. PMID:12531876 doi:10.1172/JCI16336
31. ↑ Murphy RT, Mogensen J, Shaw A, Kubo T, Hughes S, McKenna WJ. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet. 2004 Jan 31;363(9406):371-2. PMID:15070570 doi:10.1016/S0140-6736(04)15468-8
32. ↑ Yamada Y, Namba K, Fujii T. Cardiac muscle thin filament structures reveal calcium regulatory mechanism. Nat Commun. 2020 Jan 9;11(1):153. doi: 10.1038/s41467-019-14008-1. PMID:31919429 doi:http://dx.doi.org/10.1038/s41467-019-14008-1