Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

Pinto, José R.; Siegfried, Jill D.; Parvatiyar, Michelle S.; Li, Duanxiang; Norton, Nadine; Jones, Michelle; Liang, Jingsheng; Potter, James D.; Hershberger, Ray E.

doi:10.1074/jbc.m111.267211

Cited by 44 publications

(36 citation statements)

References 50 publications

(59 reference statements)

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“…The father and the proband both had a mutation identified in MYH7, the beta myosin heavy chain, so it is possible that Y5H was only an incidentally observed mutation. All of the TNNC1 mutations identified in the study yielded small changes in calcium sensitivity, but Y5H had the largest Ca 2+ desensitizing effect and also reduced the effect of PKA phosphorylation 109 . Tyr5 is located in helix N of cNTnC, where it packs against Arg83 of helix D. It is possible that the Y5H mutation creates an electrostatic repulsion that destabilizes helix N and disrupts positioning of the cNTnC domain.…”

Section: Dilated Cardiomyopathy-associated Mutationsmentioning

confidence: 83%

“…The five mutations, A8V, A31S, C84Y, E134D, and D145E were expressed recombinantly in troponin C and exchanged into porcine muscle fibers. All of the mutants except E134D were associated with increased calcium sensitivity 109–112 , so E134D may be a clinically insignificant variant. The observed increases in calcium sensitivity are consistent with what is observed in HCM-associated mutations involving other thin filament proteins 99 .…”

Section: Hypertrophic Cardiomyopathy-associated Mutationsmentioning

confidence: 98%

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Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

106

105

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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Section: Dilated Cardiomyopathy-associated Mutationsmentioning

confidence: 83%

Section: Hypertrophic Cardiomyopathy-associated Mutationsmentioning

confidence: 98%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

106

105

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“…19,69–75 For example, Li et al and Schmidtmann et al found that the cTnC L29Q mutation hindered the effect of PKA-mediated phosphorylation of cTnI on transducing the signal from cTnC to cTnI, and Dong et al reported that this mutation blunted the enhancement of NcTnC closing rate upon cTnI phosphorylation by PKA. 70–72 Using the in vitro motility assay, Deng et al reported that cTnI R145G mutation suppressed the PKA effects on the maximal vitro sliding velocity and maximal actoS1-ATPase activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation

et al. 2016

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cTnIP82S (cTnIP83S in rodents) resides at the I-T arm of cardiac troponin I (cTnI) and was initially identified as a disease-causing mutation of hypertrophic cardiomyopathy (HCM). However, later studies suggested this may not be true. We recently reported that introduction of an HCM-associated mutation in either inhibitory-peptide (cTnIR146G) or cardiacspecific N-terminus (cTnIR21C) of cTnI blunts the PKA-mediated modulation on myofibril activation/relaxation kinetics by prohibiting formation of intrasubunit contacts between these regions. Here, we tested whether this also occurs for cTnIP83S. cTnIP83S increased both Ca2+ binding affinity to cTn (KCa) and affinity of cTnC for cTnI (KC–I), and eliminated the reduction of KCa and KC–I observed for phosphorylated-cTnIWT. In isolated myofibrils, cTnIP83S maintained maximal tension (TMAX) and Ca2+ sensitivity of tension (pCa50). For cTnIWT myofibrils, PKA-mediated phosphorylation decreased pCa50 and sped up the slow-phase relaxation (especially for those Ca2+ conditions that heart performs in vivo). Those effects were blunted for cTnIP83S myofibrils. Molecular-dynamics simulations suggested cTnIP83S moderately inhibited an intrasubunit interaction formation between inhibitory-peptide and N-terminus, but this “blunting” effect was weaker than that with cTnIR146G or cTnIR21C. In summary, cTnIP83S has similar effects as other HCM-associated cTnI mutations on troponin and myofibril function even though it is in the I-T arm of cTnI.

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“…Although a few studies have reported functional studies on mutations in cTnC and have shown the effect of cTnC mutations in muscle contractility (Mogensen et al, 2004;Hershberger et al, 2010;Pinto et al, 2011), it is highly likely that cTnC being the Ca 2+ sensor of cardiac muscle, any mutations in this protein might be lethal and therefore possibly be non-existent in the adult population. Hence, it is not clear from this study whether mutations may arise as a consequence of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Assessment of DNA damage using cytokinesis-block micronucleus cytome assay in lymphocytes of dilated cardiomyopathy patients

Sitaraman

Babu²,

Badarinath

et al. 2014

Genet. Res.

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Studies on the extent of DNA damage are undertaken to elucidate the nature and causes of genomic instability in any syndrome or disease progression in human. In this study, cytokinesis-block micronucleus cytome (CBMN Cyt) assay was employed to evaluate the extent of chromosomal instability or DNA damage in lymphocytes of patients suffering from dilated cardiomyopathy (DCM), a serious cardiac muscle disorder. Effect of DNA damage on the disease was also assessed by analysis of mutations in cardiac Troponin C type I (TNNC1) gene. Blood samples were collected from 48 DCM patients and 48 age- and sex-matched controls from Vellore region of South India. Significantly high frequencies of micronuclei (MNi) and genomic damage such as nuclear buds (NBUDs) and nucleoplasmic bridges (NPBs) were observed in the patient group as compared with the control group (P < 0·001). Molecular analysis revealed that no mutations were found in the TNNC1 gene. It was observed that although there was a high frequency of DNA damage in the lymphocytes of the patients, no correlation between severity of the phenotype and the frequencies of MNi, NPBs and NBUDS could be established. Our study appears to be the first one in which chromosomal instability was estimated using CBMN Cyt assay for DCM patients. Studies with a larger population size may help in validating the use of genetic markers for establishing frequencies and type of DNA damage in DCM. It will also help in understanding the effect of DNA damage on this disease.

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Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

Cited by 44 publications

References 50 publications

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation

Assessment of DNA damage using cytokinesis-block micronucleus cytome assay in lymphocytes of dilated cardiomyopathy patients

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