Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair

Schwartz, K.

doi:10.1172/jci200319632

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…Of particular note, despite near-identical increases in the Ca 2+ sensitivity of force generation for each of the three independent Residue 92 mutations, the measured increases in the free energy of ATP hydrolysis, (representing a baseline increase in energy utilization required to perform the identical workload) were mutation-specific with regards to magnitude and likely due to precise changes in local protein-protein dynamics within the N-terminal tail domain. The net effect would be a significant decrease in contractile reserve that would be dramatically accentuated in the context of increased hemodynamic demand and potentially trigger SCD115. Moreover, the long-term energetic compromise could contribute to cardiomyopathic remodeling.…”

Section: Bridging the Gap Between Biophysics And Physiology: Animal Mmentioning

confidence: 99%

Thin Filament Mutations

Tardiff

2011

Circulation Research

135

108

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Sixteen years ago, mutations in cardiac troponin (Tn)T and ␣-tropomyosin were linked to familial hypertrophic cardiomyopathy, thus transforming the disorder from a disease of the ␤-myosin heavy chain to a disease of the cardiac sarcomere. From the outset, studies suggested that mutations in the regulatory thin filament caused a complex, heterogeneous pattern of ventricular remodeling with wide variations in clinical expression. To date, the clinical heterogeneity is well matched by an extensive array of nearly 100 independent mutations in all components of the cardiac thin filament. Significant advances in our understanding of the biophysics of myofilament activation, coupled to the emerging evidence that thin filament linked cardiomyopathies are progressive, suggests that a renewed focus on the most proximal events in both the molecular and clinical pathogenesis of the disease will be necessary to achieve the central goal of using genotype information to manage affected patients. In this review, we examine the existing biophysical and clinical evidence in support of a more proximal definition of thin filament cardiomyopathies. In addition, new high-resolution, integrated approaches are presented to help define the way forward as the field works toward developing a more robust link between genotype and phenotype in this complex disorder. (Circ Res. 2011;108:765-782.)

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Section: Bridging the Gap Between Biophysics And Physiology: Animal Mmentioning

confidence: 99%

Thin Filament Mutations

Tardiff

2011

Circulation Research

135

108

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“…As shown in Figure 3, the flexible linker domain is immediately distal to the extended Tm-cTnT binding domain that acts to stabilize the thin filament [86]. Additionally, this interaction plays an important role in determining the position of the Tn-Tm complex on actin, potentially altering efficient crossbridge cycling [76]. Therefore, alterations in the structure, position and flexibility of this region could affect both inter-and intra-protein interactions and significantly alter myofilament activation.…”

Section: An Integrative Approach To Mutations In the Ctnt Extended Flexible Linker And The Tropomyosin Overlap Domainsmentioning

confidence: 99%

Moving beyond simple answers to complex disorders in sarcomeric cardiomyopathies: the role of integrated systems

Deranek

Klass

Tardiff

2019

Pflugers Arch - Eur J Physiol

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The classic clinical definition of hypertrophic cardiomyopathy (HCM) as originally described by Teare is deceptively simple, "left ventricular hypertrophy in the absence of any identifiable cause". Longitudinal studies, however, including a seminal study performed by Frank and Braunwald in 1968, clearly described the disorder much as we know it today, a complex, progressive and highly variable cardiomyopathy affecting ~1/500 individuals worldwide. Subsequent genetic linkage studies in the early 1990's identified mutations in virtually all of the protein components of the cardiac sarcomere as the primary molecular cause of HCM. In addition, a substantial proportion of inherited dilated cardiomyopathy (DCM) has also been linked to sarcomeric protein mutations. Despite our deep understanding of the overall function of the sarcomere as the primary driver of cardiac contractility, the ability to use genotype in patient management remains elusive. A persistent challenge in the field from both the biophysical and clinical standpoints is how to rigorously link high-resolution protein dynamics and mechanics to the long-term cardiovascular remodeling process that characterizes these complex disorders. In this review, we will explore the depth of the problem from both the standpoint of a multi-subunit, highly conserved and dynamic "machine" to the resultant clinical and structural human phenotype with an emphasis on new, integrative approaches that can be widely applied to identify both novel disease mechanisms and new therapeutic targets for these primary biophysical disorders of the cardiac sarcomere. Keywordsthin filament; hypertrophic cardiomyopathy; dilated cardiomyopathy; troponin; tropomyosin Current Challenges in our Understanding of Sarcomeric CardiomyopathiesMutations in the genes that encode the protein components of the cardiac thin filament were first linked to clinical cardiomyopathies in 1994 [85]. Mutations in the regulatory thin filament comprise ~ 7-10% of hypertrophic cardiomyopathy (HCM) cases and represent a distinct and complex subset of the disorder with marked mutation-specific phenotypes [11,84]. Despite 25 years of basic research, many questions remain regarding the clinical

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Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

Gangadharan

Sunitha

Mukherjee

et al. 2017

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

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Point mutations in genes encoding sarcomeric proteins are the leading cause of inherited primary cardiomyopathies. Among them are mutations in the gene that encodes cardiac troponin T (TnT). These mutations are clustered in the tropomyosin (Tm) binding region of TnT, TNT1 (residues 80-180). To understand the mechanistic changes caused by pathogenic mutations in the TNT1 region, six hypertrophic cardiomyopathy (HCM) and two dilated cardiomyopathy (DCM) mutants were studied by biochemical approaches. Binding assays in the absence and presence of actin revealed changes in the affinity of some, but not all, TnT mutants for Tm relative to WT TnT. HCM mutants were hypersensitive and DCM mutants were hyposensitive to Ca in regulated actomyosin ATPase activities. To gain better insight into the disease mechanism, we modeled the structure of TNT1 and its interactions with Tm. The stability predictions made by the model correlated well with the affinity changes observed in vitro of TnT mutants for Tm. The changes in Ca sensitivity showed a strong correlation with the changes in binding affinity. We suggest the primary reason by which these mutations between residues 92 and 144 cause cardiomyopathy is by changing the affinity of TnT for Tm within the TNT1 region.

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Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair

Abstract: Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: familial hypertrophic cardiomyopathy (FHC); sudden cardiac death (SCD); troponin T (TnT); cardiac troponin T (cTnT); maximum rate of left ventricular pressure decay (-dP/dt).

Cited by 3 publications

References 15 publications

Thin Filament Mutations

Thin Filament Mutations

Moving beyond simple answers to complex disorders in sarcomeric cardiomyopathies: the role of integrated systems

Molecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region

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