Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

The effects of Troponin T (TnT) mutants R141W and ΔK210, the only two currently known mutations in TnT that cause dilated cardiomyopathy(DCM) independent of familial hypertrophic cardiomyopathy (FHC), and TnT-K273E, a mutation that leads to a progression from FHC to DCM, were investigated. Studies on the Ca2+ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-ΔK210 caused a significant decrease in Ca2+ sensitivity, whereas the TnT-R141W did not result in any change in Ca2+ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-ΔK210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-ΔK210 mutant decreased maximal ATPase activity in the presence of Ca2+. However, the TnT-K273E mutation caused a significant increase in Ca2+ sensitivity but behaved similarly to HCWTnT in actomyosin activation assays. Inhibition of ATPase activity in reconstituted actin-activated myosin ATPase assays was similar for all three TnT mutants and HCWTnT. Additionally, circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT. These results suggest that a rightward shift in Ca2+ sensitivity is not the only determinant for the phenotype of DCM. The effects of Troponin T (TnT) mutants R141W and ΔK210, the only two currently known mutations in TnT that cause dilated cardiomyopathy(DCM) independent of familial hypertrophic cardiomyopathy (FHC), and TnT-K273E, a mutation that leads to a progression from FHC to DCM, were investigated. Studies on the Ca2+ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-ΔK210 caused a significant decrease in Ca2+ sensitivity, whereas the TnT-R141W did not result in any change in Ca2+ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-ΔK210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-ΔK210 mutant decreased maximal ATPase activity in the presence of Ca2+. However, the TnT-K273E mutation caused a significant increase in Ca2+ sensitivity but behaved similarly to HCWTnT in actomyosin activation assays. Inhibition of ATPase activity in reconstituted actin-activated myosin ATPase assays was similar for all three TnT mutants and HCWTnT. Additionally, circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT. These results suggest that a rightward shift in Ca2+ sensitivity is not the only determinant for the phenotype of DCM. Contraction of cardiac muscle is initiated by the binding of Ca2+ to the Ca2+-specific regulatory site in Troponin C (TnC), 1The abbreviations used are: TnC, troponin C; FHC, familial hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy; WT, wild type; HCWTnT, human cardiac wild-type troponin T; CD, circular dichroism; cTnT, cardiac TnT; RLC, regulatory light chain; MOPS, 4-morpholinepropanesulfonic acid; TM, tropomyosin. the Ca2+ binding subunit of the troponin (Tn) complex, which also contains Troponin I (TnI) and Troponin T (TnT). The Tn complex, together with tropomyosin (Tm), forms the regulatory system of the contractile apparatus (1Gergely J. Adv. Exp. Med. Biol. 1998; 453: 169-176Crossref PubMed Scopus (25) Google Scholar, 2Zot A.S. Potter J.D. Annu. Rev. Biophys. Biophys. Chem. 1987; 16: 535-559Crossref PubMed Scopus (447) Google Scholar). Contraction results from the ATP-driven interaction of the thin, actin-containing filaments and the thick, myosin-containing filaments. This interaction is regulated by Tm-Tn in a Ca2+-dependent manner. Upon binding of Ca2+ to the single Ca2+-specific site of cardiac TnC, the C terminus of TnI interacts with the amino terminus of TnC and dissociates from the actin·Tm complex, allowing myosin to bind to actin. TnT is thought to stabilize the troponin complex, but it also regulates the Ca2+ sensitivity of actomyosin ATPase activity and the level of ATPase activation as well as force development (2Zot A.S. Potter J.D. Annu. Rev. Biophys. Biophys. Chem. 1987; 16: 535-559Crossref PubMed Scopus (447) Google Scholar, 3Tobacman L.S. Annu. Rev. Physiol. 1996; 58: 447-481Crossref PubMed Scopus (461) Google Scholar). Recently, mutations in genes for various sarcomeric proteins were shown to cause dilated cardiomyopathy (DCM) (4Seidman J.G. Seidman C. Cell. 2001; 104: 557-567Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar). DCM is a relatively common disorder that results in heart failure and premature death (5Cohn J.N. Bristow M.R. Chien K.R. Colucci W.S. Frazier O.H. Leinwand L.A. Lorell B.H. Moss A.J. Sonnenblick E.H. Walsh R.A. Mockrin S.C. Reinlib L. Circulation. 1997; 95: 766-770Crossref PubMed Scopus (195) Google Scholar). DCM is characterized by ventricular dilation and impaired systolic function. Pathological manifestation of DCM includes modest hypertrophy, myocyte degeneration, and increased interstitial fibrosis (4Seidman J.G. Seidman C. Cell. 2001; 104: 557-567Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar). Proposed causes of DCM include alcohol toxicity, ischemia, metabolic and nutritional deficiency, infectious diseases, and familial and genetic factors. Among these factors, it is estimated that heritable gene mutations account for 25–30% of cases (4Seidman J.G. Seidman C. Cell. 2001; 104: 557-567Abstract Full Text Full Text PDF PubMed Scopus (899) Google Scholar). The first thin filament-associated DCM mutation was described in the cardiac actin gene (6Olson T.M. Michels V.V. Thibodeau S.N. Tai Y.S. Keating M.T. Science. 1998; 280: 750-752Crossref PubMed Scopus (599) Google Scholar). Subsequently, mutations were found in other sarcomeric proteins, including β-myosin heavy chain, cardiac myosin binding protein C, titin, α-Tm, and cardiac TnT (7Fatkin D. Graham R.M. Physiol. Rev. 2002; 82: 945-980Crossref PubMed Scopus (267) Google Scholar). The presumed mechanism by which these mutations cause DCM is not clearly understood. So far there are four TnT mutations (R92W, R141W, ΔK210, and K273E) that are known to cause DCM. However, only two of these mutations (R141W and ΔK210) are known to cause DCM independent of FHC. After genotypic analysis, Kamisago et al. (8Kamisago M. Sharma S.D. DePalma S.R. Solomon S. Sharma P. McDonough B. Smoot L. Mullen M.P. Woolf P.K. Wigle E.D. Seidman J.G. Seidman C.E. N. Engl. J. Med. 2000; 343: 1688-1696Crossref PubMed Scopus (588) Google Scholar) reported the first TnT mutation as the cause of DCM in two unrelated families. This mutation occurs in exon 13 of cardiac TnT because of a deletion of the basic amino acid lysine at position 210. None of the individuals affected with DCM exhibited ventricular hypertrophy, a hallmark feature of hypertrophic cardiomyopathy. Medical records of deceased individuals from these families revealed sudden deaths of two infants with infantile cardiomyopathy and three young adults (8Kamisago M. Sharma S.D. DePalma S.R. Solomon S. Sharma P. McDonough B. Smoot L. Mullen M.P. Woolf P.K. Wigle E.D. Seidman J.G. Seidman C.E. N. Engl. J. Med. 2000; 343: 1688-1696Crossref PubMed Scopus (588) Google Scholar). Li et al. (9Li D. Czernuszewicz G.Z. Gonzalez O. Tapscott T. Karibe A. Durand J.B. Brugada R. Hill R. Gregoritch J.M. Anderson J.L. Quinones M. Bachinski L.L. Roberts R. Circulation. 2001; 104: 2188-2193Crossref PubMed Scopus (109) Google Scholar) reported another novel TnT mutation, TnT-R141W, in the Tm-binding site of TnT in a large family of 72 members. Fourteen living members of the family clinically manifested DCM, predominantly in the second decade of their life. Seventeen members of this family died of heart failure before the genotypic studies were carried out. It is worth mentioning that arginine at position 141 of cardiac TnT (cTnT) is conserved in many species, including mouse, rat, chicken, quail, and nematode as well as among the slow muscle of TnT (9Li D. Czernuszewicz G.Z. Gonzalez O. Tapscott T. Karibe A. Durand J.B. Brugada R. Hill R. Gregoritch J.M. Anderson J.L. Quinones M. Bachinski L.L. Roberts R. Circulation. 2001; 104: 2188-2193Crossref PubMed Scopus (109) Google Scholar). et al. N. M. M. T. M. T. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) reported another novel mutation in the cardiac TnT gene at position the conserved amino acid lysine is to family members from two unrelated the mutation, and this mutation is with a of sudden cardiac death in This mutation caused in of family members with the the mutation caused a from FHC to DCM in of the two family members progression was for the cardiac dilation are not clearly understood. In this the of the TnT mutations R141W, ΔK210, and on the regulatory of the thin et al. TnT-ΔK210 and that the Ca2+ of this mutation is the cause of dilated cardiomyopathy. Ca2+ is the of the thin this mutation the Ca2+ sensitivity of force results are in with which that the mutation TnT-ΔK210 caused a decrease in Ca2+ However, also a significant decrease in the maximal force in fibers when compared with which was not by et al. However, ATPase activation assays in the presence of Ca2+ for the mutants compared with HCWTnT. mutants a significant decrease in the ATPase activity when compared with HCWTnT, with the mutation a of maximal ATPase activity compared with the R141W So the caused by the TnT-R141W the TnT-K273E found that the DCM mutant TnT-R141W did not result in any change in Ca2+ sensitivity and maximal force when compared with HCWTnT. The TnT-K273E mutation the muscle to Ca2+ with These results suggest that DCM mutations the sarcomeric effects in muscle and of for human cardiac TnT was in D. R. J. M. Potter J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The R141W, and mutations were in human by the of R. Seidman J.G. in Scholar). The was to the presence of mutations to in were for of HCWTnT and mutants R141W and ΔK210, TnT-K273E, and TnI and TnC Potter J.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Potter J.D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, D. T. J. Potter J.D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the proteins was on is used to the force and the Ca2+ sensitivity of force The is of the Tn and with HCWTnT TnT mutants and with the human cardiac This is well in this D. R. J. M. Potter J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. T. Potter J.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Potter J.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). muscle were on a force and with the for The of was and Subsequently, the fibers were to and for the force The of the is the as that of the the Ca2+ was the Ca2+ sensitivity of force the fibers were to the of Ca2+ from to the Tn complex, the fibers were in a MOPS, and HCWTnT for at After a the fibers were in TnT protein for another This was to the of troponin from the fibers were with the the protein at and for the force that to the of the porcine cardiac TnI and The Ca2+ of force was with a human cardiac The with the was in the for at for the force to a fibers were in and with the the The Ca2+ sensitivity of force development was human cardiac as before by the to Ca2+ from to The was the Hill in The Hill is as force Ca2+ of the in which of force is and is the Hill of protein used in the are: with for fibers with of HCWTnT, TnT-R141W, TnT-K273E for and fibers reconstituted with with HCWTnT and the TnT The were for at in before was with a apparatus the were for at a of on the were to with a The was at and the were for in a of to binding the were with Troponin I and regulatory light in at for at After the were three with and for the were for in and was by of and in development was by in were on the by Troponin was as described by et al. M. J. PubMed Scopus Google Scholar). cardiac myosin was to et al. T. J. PubMed Scopus Google Scholar). cardiac was from to Potter J.D. PubMed Scopus Google Scholar). The Tn HCWTnT and TnT-R141W, TnT-K273E with human cardiac TnI and TnC were to the J.D. PubMed Scopus Google Scholar). three troponin and were first MOPS, and After were at a and for on before with of The MOPS, and by and Subsequently, the were of from and The TnT and TnI that at the was by at for The of the reconstituted troponin was by and was for ATPase ATPase assays were with muscle porcine cardiac and Tn as described D. R. J. M. Potter J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Potter J.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The of porcine cardiac myosin was ATPase assays were in the presence and of Ca2+. The ATPase MOPS, were initiated with After of at the was with The that was was to the of and J. Biol. Chem. Full Text PDF Google Scholar). of the HCWTnT and the TnT mutants TnT-R141W, and TnT-K273E were on a a of at in a and The was at in the far with a of at a of and at a of The of HCWTnT and the TnT mutants was by HCWTnT as a The of HCWTnT was by and of was the system were were and was The in for the was the is the in is the and is the in The for protein was the for at Biophys. PubMed Scopus Google Scholar) is the of in are as the of the was the of was at are as S.D. of in the in the porcine fibers with HCWTnT and reconstituted with human cardiac TnI cardiac TnC shown in porcine fibers and reconstituted with human Tn a decrease in Ca2+ sensitivity when compared with This result is with was in R. J. T. Potter J.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Potter J.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). This in Ca2+ sensitivity is to the of human Tn the porcine In the Ca2+ of force development for mutants was compared with the Ca2+ of force development of TnT the Ca2+ of force development was and there was significant in Ca2+ sensitivity and the of fibers used not the Ca2+ sensitivity of fibers with a significant decrease in Ca2+ sensitivity compared with fibers the Ca2+ sensitivity of fibers with TnT-R141W. The TnT-R141W mutation caused a but not significant decrease in Ca2+ sensitivity of force development when compared with also the on the Ca2+ of force development for the TnT-K273E mutation a of fibers was used for this to the of HCWTnT on these porcine with the other of a of in porcine fibers with HCWTnT. TnT-K273E was to the troponin from porcine a shift in Ca2+ sensitivity a of was I the of the and the Hill for the fibers with HCWTnT and TnT was significant in the Hill is a of HCWTnT and TnT of HCWTnT and on the sensitivity of force development and the Hill in porcine cardiac muscle in the of for the and TnT-K273E is from HCWTnT was in a of was in a of for the and TnT-K273E is from HCWTnT The for the and TnT-K273E is from HCWTnT The was in a of in a of the force as the force and the force at as in a After Tn and of the force was in described used a of fibers for the TnT-K273E mutation analysis, and the HCWTnT that used as the of force as the other of fibers used for the other mutations the for the fibers was from of The TnT-R141W and fibers change in the force when compared with the However, fibers a significant decrease in maximal force compared with fibers with HCWTnT of and did of the fibers with the fibers with mutant TnT fibers were not reconstituted with and fibers with mutant TnT and reconstituted with and for used for human cardiac and regulatory light as a that the of troponin was is a of the and reconstituted fibers for TnI and a with for The of TnI in the is as The TnI in and is to the is a that of porcine TnI is is a TnT-R141W is a is the and of TnI for TnT-R141W, ΔK210, and is the and that the TnI is that the of TnI reconstituted is for HCWTnT, for R141W, for ΔK210, and for not ATPase assays were carried in the presence and of Ca2+ to the activation and of actomyosin ATPase and activation of ATPase The myosin ATPase activity in the of was as the activity The of ATPase activity was found to similar for Tn HCWTnT TnT mutants R141W, ΔK210, and Tn the Tn HCWTnT and DCM mutants was to the ATPase activity to a similar for all four proteins TnT-R141W HCWTnT for HCWTnT for However, this in was not found to significant by shown in the the ATPase activity in the presence of Ca2+ HCWTnT and TnT The was by the Tn that the were Tn the ATPase activity did not increase and The ATPase activity in the of Tn was to the activity activity in this shown in mutants a decrease in ATPase activity compared with HCWTnT. The ATPase activity of HCWTnT was whereas the TnT-R141W mutant was and TnT-ΔK210 was Tn the TnT-K273E mutant a maximal activity of which was not from the HCWTnT. The in the of the activation of the ATPase of actomyosin ATPase activity in the presence of The of HCWTnT and TnT mutants on the activation of actomyosin ATPase activity is by troponin the at the of Tn that the maximal is shown in the The are as and and myosin were in MOPS, and the of in and is as S.D. to the activity in the of level of with level of with of HCWTnT and TnT studies were carried to the mutants affected the secondary structure of TnT The for HCWTnT at was to of The of TnT-R141W mutant was whereas the other TnT-ΔK210 and TnT-K273E, and This change in is not a significant change in secondary structure when compared with HCWTnT. The of this was to the TnT mutants far known to cause DCM the in the of muscle in other and sarcomeric proteins that the of DCM because of failure at various in the force of the in force in and increased of the to as (7Fatkin D. Graham R.M. Physiol. Rev. 2002; 82: 945-980Crossref PubMed Scopus (267) Google Scholar, J. Seidman C.E. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in sarcomeric proteins cause including FHC, and DCM. The of TnT mutations FHC characterized D. R. J. M. Potter J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. J. T. Potter J.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, C. A. S. 2000; PubMed Scopus Google Scholar, S. J. 2001; PubMed Scopus Google Scholar, L.S. D. C. C. N. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and shown that mutations in TnT predominantly increase Ca2+ sensitivity D. R. J. M. Potter J.D. J. Biol. 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So only two mutations shown to cause DCM independent of FHC. the mutations the regulatory of the thin the of the mutations in two reconstituted thin filaments and cardiac muscle Studies on the Ca2+ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-ΔK210 caused a significant decrease in Ca2+ sensitivity This mutation by two other et al. S. R. M. T. S. A. 2002; PubMed Scopus Google Scholar) this first mutation and reported a rightward shift in Ca2+ sensitivity in cardiac muscle similar results with to the Ca2+ sensitivity in the of shift was the shift by et al. S. R. M. T. S. A. 2002; PubMed Scopus Google Scholar). In addition, a decrease in the maximal force for fibers with significant change in when compared with HCWTnT and This is the first of this TnT-ΔK210 mutation a decrease in maximal because decrease in maximal force was by et al. S. R. M. T. S. A. 2002; PubMed Scopus Google Scholar). also the of TnT-ΔK210 to and myosin ATPase activity in reconstituted thin to these of the Tn the TnT deletion mutant are found that the TnT-ΔK210 was to ATPase activity as at as the HCWTnT TnT-ΔK210 is in a of TnT that to TnI as well as TnC and However, it is on from the reported structure of Tn S. A. Biophys. J. 2002; Full Text Full Text PDF PubMed Scopus Google that this of TnT not bind to the of TnI as not the activity of However, found that the maximal ATPase activity in Tn the deletion mutation was decreased when compared with Tn HCWTnT Tn the TnT-ΔK210 a decrease in to myosin to in the presence of These results are in with by et al. P. M. A. R. S. C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) also the TnT-ΔK210 mutation and found that the mutation caused activation at when compared with wild also in the of Tn this mutation to ATPase with It shown by that Ca2+ binding to TnC, in to of ATPase interaction with TnT J.D. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). studies by et al. J. T. PubMed Scopus Google Scholar) suggest that the lysine in TnT a with The of of these lysine decrease the of TnC for in in TnT and TnC, in a change in the of TnC for Ca2+. It is that the TnT-ΔK210 impaired the ATPase by the of of force force Ca2+ for this the to studies far reported on the of the other DCM TnT-R141W. of the TnT-R141W mutation that this mutation behaved from the TnT-ΔK210 mutation with to the Ca2+ sensitivity of force development TnT-R141W a but not significant decrease in the Ca2+ sensitivity when compared with In addition, the R141W mutation did not cause a change in maximal force when compared with HCWTnT et al. S. R. M. T. S. A. 2002; PubMed Scopus Google Scholar) that a decrease in Ca2+ sensitivity was the cause of DCM. However, the results from the TnT-R141W mutant suggest that this not the for all In ATPase found that the TnT-R141W mutation was also to the ATPase activity This is similar to was with HCWTnT and TnT-ΔK210 that the mutations are not the of did not a significant decrease in Ca2+ sensitivity of force a significant decrease in maximal ATPase activity by TnT-R141W when compared with Tn HCWTnT. However, the decrease in maximal ATPase activity by TnT-R141W mutant was when compared with TnT-ΔK210 for this that the TnT-R141W mutation is in the of TnT that to only many mutations the binding of FHC mutant occurs amino of the TnT-R141W et al. T. S. Biophys. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) mutations in a TnT and found that mutations and impaired of FHC mutations in this to a and were to stabilize the mutations the did not the function. Recently, it shown by et al. A. L.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that and Tn on conserved TnT in the cardiac TnT to in The R141W mutation is two from this and cause in this that the The decreased ATPase activity for mutants result in the systolic in with these was carried to the mutants affected the secondary structure of TnT was found the of TnT-R141W and TnT-ΔK210 when compared with wild-type TnT the in of the TnT-ΔK210 for the The S.D. for wild-type TnT was on three independent which to of It is also that the TnT-R141W mutation causes in structure that are not at the secondary structure It is not known of the mutants are affected by these other TnT mutations that cause and are of However, these mutations first cause FHC, which to DCM N. M. M. T. M. T. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, N. M. M. T. 2001; PubMed Scopus Google Scholar). of these mutations to these FHC to mutations are to The TnT-K273E, a mutation in leads to as well as DCM in affected in individuals with hypertrophy, the to DCM. It is not to this from to In the TnT-K273E mutation the muscle to The shift in sensitivity is with other The this mutation exhibited cardiac et al. C. Leinwand L.A. J. Physiol. 2001; 280: PubMed Google Scholar) shown that this of from FHC to DCM is also in with the mutation in the cardiac heavy chain, which that FHC and DCM of the is a of sudden cardiac death in infants as well as adults among the TnT-ΔK210 mutation (8Kamisago M. Sharma S.D. DePalma S.R. Solomon S. Sharma P. McDonough B. Smoot L. Mullen M.P. Woolf P.K. Wigle E.D. Seidman J.G. Seidman C.E. N. Engl. J. Med. 2000; 343: 1688-1696Crossref PubMed Scopus (588) Google Scholar). The decreased ATPase activity and Ca2+ sensitivity as well as impaired force that the for the to to DCM. The the two DCM mutations in this with the by the The exhibited by the TnT-R141W mutation are from the TnT-ΔK210 the TnT-R141W mutation also causes DCM in the affected None of the family members ventricular that DCM occurs in this family independent of FHC. The that this mutation did not cause sudden cardiac death (9Li D. Czernuszewicz G.Z. Gonzalez O. Tapscott T. Karibe A. Durand J.B. Brugada R. Hill R. Gregoritch J.M. Anderson J.L. Quinones M. Bachinski L.L. Roberts R. Circulation. 2001; 104: 2188-2193Crossref PubMed Scopus (109) Google Scholar). only of the the TnT-R141W mutation of the hallmark of DCM, which are impaired and systolic function. The of the caused by the TnT-R141W DCM mutation in is with to The in results suggest that the R141W mutation cause a DCM phenotype the It is that the of the mutation the of the the of TnT the two DCM mutations in of the TnT to in a Ca2+ is the of the thin to muscle in the Ca2+ sensitivity of force development in are to the regulatory of thin These results suggest that a decrease in Ca2+ sensitivity is to a common in the of DCM caused by TnT