Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy

Mogensen, Jens; Murphy, Ross T.; Shaw, Tony; Bahl, Ajay; Redwood, Charles; Watkins, Hugh; Burke, Margaret; Elliott, Perry; McKenna, William J.

doi:10.1016/j.jacc.2004.08.027

Cited by 209 publications

(109 citation statements)

References 30 publications

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“…We recently demonstrated a set of mutations in TNNC1 linked to HCM with the potential to disrupt myocardial contractility (23). Before this report, only two mutations in TNNC1 had been linked to DCM (6,7,18). The G159D (6, 7) and Q50R (18) mutations have been shown to segregate among family members.…”

Section: Discussionmentioning

confidence: 96%

“…Functionally, DCM troponin mutations manifest distinctively as decreased Ca 2ϩ sensitivity, reduced thin filament Ca 2ϩ affinity, and decreased in vitro cross-bridge cycling rate (4). The first DCM-causing mutation identified in TNNC1, G159D, was found in three families (6,7). In functional studies, G159D showed little-to-no decrease in myofilament Ca 2ϩ sensitivity (8 -10) but an ablated response to PKA phosphorylation (9).…”

mentioning

confidence: 99%

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Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

Pinto

Siegfried

Parvatiyar

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

Pinto

Siegfried

Parvatiyar

et al. 2011

Journal of Biological Chemistry

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“…The diagnosis of family members affected with another CTnC mutation (G159D) associated with DCM ranged from 20 to 62 years of age with the pathogenicity ranging from moderate to severe (27,28). Although no segregation and penetrance data are available for the E59D/D75Y mutation, the variable penetrance associated with G159D suggests that CTnC mutations, like other sarcomeric mutations, are governed by multifactorial processes (i.e.…”

Section: Discussionmentioning

confidence: 99%

A Dilated Cardiomyopathy Troponin C Mutation Lowers Contractile Force by Reducing Strong Myosin-Actin Binding

Dweck¹,

Reynaldo

Pinto³

et al. 2010

Journal of Biological Chemistry

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In this study we explore the mechanisms by which a double mutation (E59D/D75Y) in cardiac troponin C (CTnC) associated with dilated cardiomyopathy reduces the Ca 2؉ -activated maximal tension of cardiac muscle. Studying the single mutants (i.e. E59D or D75Y) indicates that D75Y, but not E59D, causes a reduction in the calcium affinity of CTnC in troponin complex, regulated thin filaments (RTF), and the Ca 2؉ sensitivity of contraction and ATPase in cardiac muscle preparations. However, both D75Y and E59D are required to reduce the actomyosin ATPase activity and maximal force in muscle fibers, indicating that E59D enhances the effects of D75Y. Part of the reduction in force/ATPase may be due to a defect in the interactions between CTnC and cardiac troponin T, which are known to be necessary for ATPase activation. An additional mechanism for the reduction in force/ATPase comes from measurements of the binding stoichiometry of myosin subfragment-1 (S-1) to the RTF. Using wild type RTFs, 4.8 mol S-1 was bound per mol filament (seven actins), whereas with E59D/D75Y RTFs, the number of binding sites was reduced by ϳ23% to 3.7. Altogether, these results suggest that the reduction in force and ATPase activation is possibly due to a thin filament conformation that promotes fewer accessible S-1-binding sites. In the absence of any family segregation data, the functional results presented here support the concept that this is likely a dilated cardiomyopathy-causing mutation.

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“…Mutations associated with FHC and DCM have been identified in 10 different genes encoding cardiac sarcomeric proteins, including titin, myosin-binding protein-C, ␤-cardiac myosin heavy chain, the essential and regulatory myosin light chains, ␣-cardiac actin, ␣-tropomyosin, cTnT, cTnI, and cTnC (26,27). A single mutation of G159D and a double mutation E59D/D75Y in human cTnC have been reported to associate with DCM (28) and mutation L29Q has been identified to associate with FHC (29). Within cTnC, leucine 29 is located at the junction of helix A and the nonfunctional Ca 2ϩ binding loop I, and is important for the integrity of helix A and the pseudo Ca 2ϩ binding site I (30).…”

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confidence: 99%

Structural Kinetics of Cardiac Troponin C Mutants Linked to Familial Hypertrophic and Dilated Cardiomyopathy in Troponin Complexes

Dong

Xing

Ouyang

et al. 2008

Journal of Biological Chemistry

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The key events in regulating cardiac muscle contraction involve Ca 2؉ binding to and release from cTnC (troponin C) and structural changes in cTnC and other thin filament proteins triggered by Ca 2؉ movement. Single mutations L29Q and G159D in human cTnC have been reported to associate with familial hypertrophic and dilated cardiomyopathy, respectively. We have examined the effects of these individual mutations on structural transitions in the regulatory N-domain of cTnC triggered by Ca 2؉ binding and dissociation. This study was carried out with a double mutant or triple mutants of cTnC, reconstituted into troponin with tryptophanless cTnI and cTnT. The double mutant, cTnC(L12W/N51C) labeled with 1,5-IAEDANS at Cys-51, served as a control to monitor Ca 2؉ -induced opening and closing of the N-domain by Förster resonance energy transfer (FRET). The triple mutants contained both L12W and N51C labeled with 1,5-IAEDANS, and either L29Q or G159D. Both mutations had minimal effects on the equilibrium distance between Trp-12 and Cys-51-AEDANS in the absence or presence of bound Ca 2؉ . L29Q had no effect on the closing rate of the N-domain triggered by release of Ca 2؉ , but reduced the Ca 2؉ -induced opening rate. G159D reduced both the closing and opening rates. Previous results showed that the closing rate of cTnC N-domain triggered by Ca 2؉ dissociation was substantially enhanced by PKA phosphorylation of cTnI. This rate enhancement was abolished by L29Q or G159D. These mutations alter the kinetics of structural transitions in the regulatory N-domain of cTnC that are involved in either activation (L29Q) or deactivation (G159D). Both mutations appear to be antagonistic toward phosphorylation signaling between cTnI and cTnC.Contraction of cardiac muscle is activated by the binding of Ca 2ϩ to the Ca 2ϩ -binding subunit troponin C (cTnC) 2 of the trimeric troponin complex. cTnC, the other two troponin subunits (troponin I (cTnI) and troponin T (cTnT)) and tropomyosin form the regulatory system of the contractile apparatus. These proteins are located in the thin filament. Contraction occurs when the myosin head in the thick filament interacts with actin causing the two filaments to slide past each other. The troponin complex in the thin filament regulates the actinmyosin interaction. Ca 2ϩ binding to the single site in the N-domain of cTnC initiates the activation process. cTnC has two globular regions, an N-terminal domain and a C-terminal domain. The N-domain has only one Ca 2ϩ binding site (site II) and the C-domain contains two binding site (binding sites III and IV). Ca 2ϩ binding to site II in the presence of cTnI induces an open conformation of the N-domain to expose a hydrophobic patch in the domain (1-3). Once exposed, the hydrophobic patch binds strongly with the regulatory region of cTnI. This strong interaction pulls cTnI away from actin and relieves the inhibition of actomyosin ATPase and muscle contraction. This regulation process is further fine-tuned with phosphorylation of cTnI serine 23 and serine 24...

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Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy

Cited by 209 publications

References 30 publications

Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

A Dilated Cardiomyopathy Troponin C Mutation Lowers Contractile Force by Reducing Strong Myosin-Actin Binding

Structural Kinetics of Cardiac Troponin C Mutants Linked to Familial Hypertrophic and Dilated Cardiomyopathy in Troponin Complexes

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