The cardiac myosin heavy chain Arg-403→Gln mutation that causes hypertrophic cardiomyopathy does not affect the actin- or ATP-binding capacities of two size-limited recombinant myosin heavy chain fragments

Eldin, Patrick; Cunff, Martine Le; Mornet, Dominique; Léger, Jean J.

doi:10.1042/bj3060345

Cited by 4 publications

(1 citation statement)

References 38 publications

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“…81 Mutant myosin heavy chain fragments were produced and shown to bind ATP normally 81, 82 , but to have reduced ATPase activity and in vitro actin-sliding motility in comparison to wildtype fragments 81 . Ex vivo analyses of myosins isolated from skeletal muscles of HCM patients 83 similarly showed abnormal actin-myosin interactions.…”

Section: Harnessing Mutations To Probe Mechanismmentioning

confidence: 99%

Identifying Sarcomere Gene Mutations in Hypertrophic Cardiomyopathy

Seidman

2011

Circulation Research

246

194

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This article provides an historical and personal perspective on the discovery of genetic causes for hypertrophic cardiomyopathy (HCM). Extraordinary insights of physicians who initially detailed remarkable and varied manifestations of the disorder, collaboration among multidisciplinary teams with skills in clinical diagnostics and molecular genetics, and hard work by scores of trainees, solved the etiologic riddle of HCM, and unexpectedly demonstrated mutations in sarcomere protein genes as the cause of disease. In addition to celebrating 20 years of genetic research in HCM, this article serves as an introductory overview to a thematic review series that will present contemporary advances in the field of hypertrophic heart disease. Through the continued application of advances in genetic methodologies, combined with biochemical and biophysical analyses of the consequences of human mutations, fundamental knowledge about HCM and sarcomere biology has emerged. Expanding research to elucidate the mechanisms by which subtle genetic variation in contractile proteins remodel the human heart remains an exciting opportunity, one with considerable promise to provide new strategies to limit or even prevent HCM pathogenesis.

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Section: Harnessing Mutations To Probe Mechanismmentioning

confidence: 99%

Identifying Sarcomere Gene Mutations in Hypertrophic Cardiomyopathy

Seidman

2011

Circulation Research

246

194

View full text Add to dashboard Cite

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Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy

Redwood¹

1999

Cardiovascular Research

165

123

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Hypertrophic cardiomyopathy (HCM) is one of the most frequently occurring inherited cardiac disorders, affecting up to 1 in 500 of the population. Molecular genetic analysis has shown that HCM is a disease of the sarcomere, caused by mutations in certain contractile protein genes. To date seven disease-associated genes have been identified, those encoding beta-myosin heavy chain, both regulatory and essential myosin light chains, myosin binding protein-C, cardiac troponin T, cardiac troponin I and alpha-tropomyosin. Here we review the analyses of how these mutations affect the in vitro contractile protein function and the hypotheses derived to explain the development of the disease state.

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Palmiter

Tyska

Haeberle

et al. 2000

Journal of Muscle Research and Cell Motility

125

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Familial hypertrophic cardiomyopathy (FHC) is a disease of the sarcomere. In the beta-myosin heavy chain gene, which codes for the mechanical enzyme myosin, greater than 40 point mutations have been found that are causal for this disease. We have studied the effect of two mutations, the R403Q and L908V, on myosin molecular mechanics. In the in vitro motility assay, the mutant myosins produced a 30% greater velocity of actin filament movement (v(actin)). At the single molecule level, v(actin) approximately d/t(on), where d is the myosin unitary step displacement and t(on) is the step duration. Laser trap studies were performed at 10 microM MgATP to estimate d and t(on) for the normal and mutant myosin molecules. The increase in v(actin) can be explained by a significant decrease in the average t(on)'s in both the R403Q and L908V mutants (approximately 30 ms) compared to controls (approximately 40 ms), while d was not different for all myosins tested (approximately 7 nm). Thus the mutations affect the kinetics of the cross-bridge cycle without any effect on myosin's inherent motion and force generating capacity. Based on these studies, the primary signal for the hypertrophic response appears to be an apparent gain in function of the individual mutant myosin molecules.

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The cardiac myosin heavy chain Arg-403→Gln mutation that causes hypertrophic cardiomyopathy does not affect the actin- or ATP-binding capacities of two size-limited recombinant myosin heavy chain fragments

Cited by 4 publications

References 38 publications

Identifying Sarcomere Gene Mutations in Hypertrophic Cardiomyopathy

Identifying Sarcomere Gene Mutations in Hypertrophic Cardiomyopathy

Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy

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