Novel mutations in sarcomeric protein genes in dilated cardiomyopathy

Daehmlow, Steffen; Erdmann, Jeanette; Knueppel, Tanja; Gille, Christoph; Froemmel, Cornelius; Hummel, Manfred; Hetzer, Roland; Regitz‐Zagrosek, Vera

doi:10.1016/s0006-291x(02)02374-4

Cited by 139 publications

(100 citation statements)

References 24 publications

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“…29 and 38. In brief, actin-activated ATPase activities of myosin (100-400 nM) isolated from a single heart were measured through colorimetric determination of P i release at multiple actin concentrations between 5 Actin filament velocities (V actin ) were determined in an in vitro motility assay (12,15) through manual filament tracking software (13) at 1 mM ATP in low-salt actin buffer (0.025 M imidazole͞0.004 M MgCl 2 ͞0.01 M DTT͞0.001 M EGTA͞0.025 M KCl, pH 7.4) at 30°C, and 100 g͞ml monomeric myosin was added to the flow-cell chamber. Video images were digitized at three frames per s so that actin filaments moved no more than half their length between images.…”

Section: )mentioning

confidence: 99%

“…Dilated hearts are hypocontractile, with systolic dysfunction leading to a reduced ejection fraction: a hallmark of a failing heart (2, 3). Only recently have autosomal dominant missense mutations to the ␤-cardiac myosin heavy chain (MHC) been identified that result in DCM (5,6). Because the primary defect resides within the heart's molecular motor, we hypothesized that altered cardiac contractile function in DCM hearts might reflect changes in the mutant myosin's ability to generate force and motion as it cyclically interacts with actin during its hydrolysis of ATP.…”

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confidence: 99%

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Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Schmitt

Debold²,

Ahmad³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

108

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Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the ␣-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V actin) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V actin in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.animal models ͉ biophysics ͉ genetics ͉ single molecule ͉ laser trap D ilated cardiomyopathy (DCM) is an early step in the pathway leading to heart failure, the leading cause of human morbidity and mortality (1, 2). Although etiological factors such as ischemia and diabetes can result in DCM, at least 30% of cases are genetic in origin, with mutations found in sarcomeric proteins associated with the cytoskeletal and contractile systems (3). Clinically, DCM is characterized by myocardial hypertrophy, thin-walled ventricles, and myocyte hypoplasia (2, 4). Dilated hearts are hypocontractile, with systolic dysfunction leading to a reduced ejection fraction: a hallmark of a failing heart (2, 3). Only recently have autosomal dominant missense mutations to the ␤-cardiac myosin heavy chain (MHC) been identified that result in DCM (5, 6). Because the primary defect resides within the heart's molecular motor, we hypothesized that altered cardiac contractile function in DCM hearts might reflect changes in the mutant myosin's ability to generate force and motion as it cyclically interacts with actin during its hydrolysis of ATP.To investigate the impact of two distinct DCM-causing MHC mutations (S532P and F764L) on cardiac myosin's molecular performance, we have genetically engineered these missense mutations separately into the murine ␣-cardiac MHC gene, the human ␤-MHC homolog, to generate two separate DCM knockin mouse models. In addition to cardiac dilation and dysfunction, defects in isolated myocyte contractility were observed that are consistent with DCM. Interestingly, defects at the whole-heart and cellular levels were cor...

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Section: )mentioning

confidence: 99%

mentioning

confidence: 99%

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Schmitt

Debold²,

Ahmad³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Additional DCM mutations that cause early-onset ventricular dilation have been identified (28,216,224). A genomewide linkage analysis on patients suffering from familial DCM by Kamisago et al (216) indicated disease-causing gene mutations in myofibrillar proteins, including β-MHC, cTnT, cTnI and α-TM, which account for approximately 10% of the cases of familial DCM.…”

Section: Hypertrophic Cardiomyopathymentioning

confidence: 99%

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Macháčková¹,

Barta²,

Dhalla³

2006

Canadian Journal of Cardiology

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“…Although genes encoding sarcomeric proteins were traditionally considered to be involved in hypertrophic cardiomyopathy, 17 since 1998 it has also been known that mutations in these genes can cause IDC. 18 Thus, mutations in the genes coding for the a-and b-myosin heavy chains, 19 a-cardiac actin, 18 a-tropomyosin, 20 troponin T, 21 troponin I, 22 troponin C, 23 titin, 24 myosin-binding protein C 25 and telethonin 10 have been shown to cause IDC.…”

Section: Introductionmentioning

confidence: 99%

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

et al. 2009

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We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.

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Novel mutations in sarcomeric protein genes in dilated cardiomyopathy

Cited by 139 publications

References 24 publications

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

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