Altered Regulation of Cardiac Muscle Contraction by Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy

Szczêsna, Danuta; Zhang, Ren; Zhao, Jiaju; Jones, Michelle; Guzman, Georgianna; Potter, James D.

doi:10.1074/jbc.275.1.624

Cited by 143 publications

(166 citation statements)

References 51 publications

(52 reference statements)

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“…The 2.3-fold higher Ca 2ϩ sensitivity in mouse E99K actin-containing thin filaments may be compared with values of 2.0 -2.1-fold with troponin T mutations, measured by IVMA and around 1.5-fold for troponin I mutations measured by ATPase assay (21, 22, 38, 41). The 1.3-fold higher Ca 2ϩ sensitivity of isometric force in ACTC E99K papillary muscle compares with a mean 1.23-fold higher Ca 2ϩ sensitivity observed with a series of seven different HCM mutations in TnI and TnT (21,36,42,43). The increase in Ca 2ϩ sensitivity was less with the human heart E99K actin (1.3-fold), which may reflect the lower mutant actin content compared with the mouse E99K actin (Fig.…”

Section: Actc E99k Mouse Model Of Hcm-we Developed Thementioning

confidence: 94%

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Song

Dyer

Stuckey

et al. 2011

Journal of Biological Chemistry

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We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca 2؉ sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca 2؉ sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to ␤-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca 2؉ sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

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Section: Actc E99k Mouse Model Of Hcm-we Developed Thementioning

confidence: 94%

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Song

Dyer

Stuckey

et al. 2011

Journal of Biological Chemistry

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“…The functional consequences of TnT mutations causing FHC have been extensively characterized (12,17,(25)(26)(27). Previously, our laboratory and others have shown that FHC-causing mutations in TnT predominantly increase myofilament Ca 2ϩ sensitivity (12,25,28).…”

Section: Discussionmentioning

confidence: 99%

“…The experiment is performed after displacement of the endogenous Tn complex and replacement with HCWTnT or TnT mutants and reconstitution with the human cardiac TnI⅐TnC complex. This protocol is well established in this laboratory (12,17,18). Porcine muscle fiber bundles were mounted on a force transducer and treated with the pCa 8.0 relaxing solution containing 1% Triton X-100 for ϳ1 h. The composition of pCa 8.0 solution was 10 Ϫ8 M Ca 2ϩ , 1 mM Mg 2ϩ , 7 mM EGTA, 5 mM MgATP, 20 mM imidazole, pH 7.0, 20 mM creatinine phosphate, and 15 units/ml creatinine phosphokinase; ionic strength ϭ 150 mM.…”

Section: Methodsmentioning

confidence: 99%

“…ATPase Assays-The ATPase assays were performed with rabbit skeletal muscle F-actin (3.5 M) containing porcine cardiac Tm (1 M) and preformed Tn complexes (1 M) as previously described (12,18). The concentration of porcine cardiac myosin was 0.6 M. All ATPase assays were performed in the presence (0.5 mM CaCl 2 ) and absence (1 mM EGTA) of Ca 2ϩ .…”

Section: Methodsmentioning

confidence: 99%

“…Mutation, Expression, and Purification of Cardiac TnT-The cDNA for human cardiac TnT was previously cloned in our laboratory (12). The TnT-⌬K210, R141W, and K273E mutations were introduced in human cTnT by the method of sequential overlapping PCR (13).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

Venkatraman

Harada

Gomes

et al. 2003

Journal of Biological Chemistry

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The effects of Troponin T (TnT) mutants R141W and ⌬K210, 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 Ca 2؉ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-⌬K210 caused a significant decrease in Ca 2؉ sensitivity, whereas the TnT-R141W did not result in any change in Ca 2؉ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-⌬K210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-⌬K210 mutant decreased maximal ATPase activity in the presence of Ca 2؉ . However, the TnT-K273E mutation caused a significant increase in Ca 2؉ 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 Ca 2؉ sensitivity is not the only determinant for the phenotype of DCM.

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Natural history and clinical outcomes of patients with hypertrophic cardiomyopathy from thin filament mutations

Saul,

Bui,

Argiro

et al. 2024

ESC Heart Failure

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Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM‐Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM‐Thin to better understand the natural history and clinical outcomes of this disease. A literature review of HCM‐Thin identified 21 studies with a total of 177 patients that were suitable for analysis. There were three outcomes of interest, which included a heart failure composite, a ventricular arrhythmia composite and a heart failure and arrhythmia composite outcome. Kaplan–Meier (KM) survival analyses for freedom from each of the abovementioned composite outcomes were completed for the entire cohort and stratified by age of onset and sarcomeric variant. The heart failure composite occurred in 24 (13.6%) patients, the ventricular arrhythmia composite occurred in 30 patients (16.9%) and the combined heart failure and arrhythmia composite occurred in 50 patients (28.2%). In regard to left ventricular ejection fraction (LVEF), the majority of patients were preserved (LVEF > 50%) compared with mildly reduced (LVEF 41%–50%) and reduced (LVEF ≤ 40%) (respectively 26.6% vs. 0.6% vs. 3.4%). The median maximal left ventricular wall thickness (LVWT) was 19.0 mm [interquartile range (IQR) 5.3]. Only 10.7% of the cohort had evidence of left ventricular outflow tract (LVOT) obstruction. Those with paediatric‐onset HCM had earlier onset and were at higher risk for each endpoint than their adult counterparts. When stratified by genetic variant, patients with TNNI3 and TPM1 were at a higher risk of the heart failure composite endpoint and the combined heart failure and arrhythmia composite endpoint in comparison with those with the other genetic variants. HCM‐Thin is associated with significant morbidity and mortality, with a high arrhythmia burden despite low rates of cardiac obstruction and mild hypertrophy. The paediatric onset of disease and certain sarcomeric variants appear to be associated with a worse prognosis than their adult‐onset and other sarcomeric variant counterparts. HCM‐Thin seems to have a distinct phenotype, which may require a different management approach.

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Altered Regulation of Cardiac Muscle Contraction by Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy

Cited by 143 publications

References 51 publications

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

Natural history and clinical outcomes of patients with hypertrophic cardiomyopathy from thin filament mutations

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