Disease-Modifying Mutations in Familial Hypertrophic Cardiomyopathy

Hilfiker‐Kleiner, Denise; Knöll, Ralph

doi:10.1161/circulationaha.108.767657

Cited by 11 publications

(6 citation statements)

References 21 publications

(27 reference statements)

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“…65; 66 Typical HCM disease is asymptomatic at onset, and clinical presentation of symptoms is frequently severe (gross hypertrophy of the left ventricle, arrhythmia, impaired blood movement and/or death). 67 Several mechanisms have been proposed to explain the events leading to the onset of hypertrophy in HCM patients, with many directly or indirectly related to impaired handling of Ca 2+ signaling or sensitivity.…”

Section: The Role Of Coupled Binding and Folding In Cardiomyopathymentioning

confidence: 99%

Order–Disorder Transitions in the Cardiac Troponin Complex

Metskas

Rhoades

2016

Journal of Molecular Biology

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The troponin complex is a molecular switch that ties shifting intracellular calcium concentration to association and dissociation of actin and myosin, effectively allowing excitation-contraction coupling in striated muscle. Although there is a long history of muscle biophysics and structural biology, many of the mechanistic details that enable troponin’s function remain incompletely understood. This review summarizes the current structural understanding of the troponin complex on the muscle thin filament, focusing on conformational changes in flexible regions of the troponin I subunit. In particular, we focus on order-disorder transitions in the C-terminal domain of troponin I, which have important implications in cardiac disease, and could also have potential as a model system for the study of coupled binding and folding.

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Section: The Role Of Coupled Binding and Folding In Cardiomyopathymentioning

confidence: 99%

Order–Disorder Transitions in the Cardiac Troponin Complex

Metskas

Rhoades

2016

Journal of Molecular Biology

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“…Thus, in humans, homozygosity for a mutation that would normally produce HCM when heterozygous is instead associated with DCM 31. Furthermore, in mice, heterozygosity in two genes, each of which individually produces HCM, does not in fact cause HCM but rather results in a DCM‐like phenotype 32,33. As such, genetically modified animal models can provide information useful to understand the relative contribution of cardiac myocyte hypertrophy (either in diameter or in length) and disproportionate tissue remodelling in the pathological phenotype.…”

Section: Cellular and Tissue Events Leading To Myocardial Remodellingmentioning

confidence: 99%

Towards a re‐definition of ‘cardiac hypertrophy’ through a rational characterization of left ventricular phenotypes: a position paper of the Working Group ‘Myocardial Function’ of the ESC

Knöll

Iaccarino

Tarone

et al. 2011

European J of Heart Fail

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Many primary or secondary diseases of the myocardium are accompanied with complex remodelling of the cardiac tissue that results in increased heart mass, often identified as cardiac 'hypertrophy'. Although there have been numerous attempts at defining such 'hypertrophy', the present paper delineates the reasons as to why current definitions of cardiac hypertrophy remain unsatisfying. Based on a brief review of the underlying pathophysiology and tissue and cellular events driving myocardial remodelling with or without changes in heart dimensions, as well as current techniques to detect such changes, we propose to restrict the use of the currently popular term 'hypertrophy' to cardiac myocytes that may or may not accompany the more complex tissue rearrangements leading to changes in shape or size of the ventricles, more broadly referred to as 'remodelling'. We also discuss the great potential of genetically modified (mouse) models as tools to define the molecular pathways leading to the different forms of left ventricle remodelling. Finally, we present an algorithm for the stepwise assessment of myocardial phenotypes applicable to animal models using well-established imaging techniques and propose a list of parameters most suited for a critical evaluation of such pathophysiological phenomena in mouse models. We believe that this effort is the first step towards a much auspicated unification of the terminology between the experimental and the clinical cardiologists.--

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“…In the cardiac troponin complex, point mutations throughout TnI C are associated with familial hypertrophic cardiomyopathy, highlighting the critical function associated with these conformational changes. 15,16 …”

Section: Introductionmentioning

confidence: 99%

“…Muscle relaxation thus requires coupled binding and folding of TnI C as it returns to its thin filament-bound state. In the cardiac troponin complex, point mutations throughout TnI C are associated with familial hypertrophic cardiomyopathy, highlighting the critical function associated with these conformational changes. , …”

Section: Introductionmentioning

confidence: 99%

Conformation and Dynamics of the Troponin I C-Terminal Domain: Combining Single-Molecule and Computational Approaches for a Disordered Protein Region

Metskas

Rhoades

2015

J. Am. Chem. Soc.

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In recent years, single-molecule Förster resonance energy transfer (smFRET) has emerged as a critical and flexible tool in structural biology, particularly in the study of highly dynamic regions and molecular assemblies. The usefulness of smFRET can be further extended by combining it with computational approaches, marrying the coarse-grained experimental data with higher-resolution in silico calculations. Here we use smFRET to determine six pairwise distances within the intrinsically disordered C-terminal domain of the troponin I subunit (TnIC) of the cardiac troponin complex. We used published conflicting structures of TnIC as starting models for molecular dynamics simulations, which were validated through successful comparison with smFRET measurements before extracting information on conformational dynamics. We flnd that pairwise distances between residues fluctuate widely in silico, but simulations are generally in good agreement with longer time scale smFRET measurements after averaging across time. Finally, Monte Carlo simulations establish that the lower-energy conformers of TnIC are indeed varied, but that the highest-sampled clusters resemble the published, conflicting models. In this way, we flnd that the controversial structures are simply stabilized local minima of this dynamic region, and a population including all three would still be consistent with spectroscopic measurements. Taken together, the combined approaches described here allow us to critically evaluate existing models of TnIC, giving insight into the conformation and dynamics of TnIC’s disordered state prior to its probable disorder–order transition. Moreover, they provide a framework for combining computational and experimental methods with diflerent time scales for the study of disordered and dynamic protein states.

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Disease-Modifying Mutations in Familial Hypertrophic Cardiomyopathy

Cited by 11 publications

References 21 publications

Order–Disorder Transitions in the Cardiac Troponin Complex

Order–Disorder Transitions in the Cardiac Troponin Complex

Towards a re‐definition of ‘cardiac hypertrophy’ through a rational characterization of left ventricular phenotypes: a position paper of the Working Group ‘Myocardial Function’ of the ESC

Conformation and Dynamics of the Troponin I C-Terminal Domain: Combining Single-Molecule and Computational Approaches for a Disordered Protein Region

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