Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes

Tadros, Hanna J.; Life, Chelsea; García, Gustavo; Pirozzi, Elisa J.; Jones, Edward G.; Datta, Susmita; Parvatiyar, Michelle S.; Chase, Prescott B.; Allen, Hugh D.; Kim, Jeffrey; Pinto, José R.; Landstrom, Andrew P.

doi:10.1016/j.yjmcc.2020.04.005

Cited by 36 publications

(30 citation statements)

References 57 publications

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“…Therefore, amino acid variations affecting Ca 2+ -binding affinity of cTnC can instigate cardiac dysfunction and pathological remodeling of the ventricular walls, typically in the form of dilated, hypertrophic, or restrictive cardiomyopathy (DCM, HCM, or RCM, respectively). 5,6 The overall structure of cTnC consists of two globular domains, each containing EF-hand motifs comprised of helixloop-helix structures that bind Ca 2+ and/or Mg 2+ . The two domains of cTnC are connected by an intrinsically disordered structure, the D/E linker.…”

Section: Introductionmentioning

confidence: 99%

Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy

et al. 2021

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“…The cardiac troponin I gene is the main target for RCM mutations in the sarcomere [ 52 ]. The mutations, mostly leading to single amino acid replacements, are concentrated in cTnI in the regulatory C-terminal regions of the protein ( Table 1 , Figure 4 ) [ 117 ]. There are two actin binding regions in the cTnI C-terminus: the inhibitory domain (aa130–150) together with the switch domain (aa151–167), and the mobile region (aa168–210).…”

Section: Molecular Mechanisms In Rcmmentioning

confidence: 99%

Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach

Cimiotti

Budde

Hassoun

et al. 2021

IJMS

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The sarcomere as the smallest contractile unit is prone to alterations in its functional, structural and associated proteins. Sarcomeric dysfunction leads to heart failure or cardiomyopathies like hypertrophic (HCM) or restrictive cardiomyopathy (RCM) etc. Genetic based RCM, a very rare but severe disease with a high mortality rate, might be induced by mutations in genes of non-sarcomeric, sarcomeric and sarcomere associated proteins. In this review, we discuss the functional effects in correlation to the phenotype and present an integrated model for the development of genetic RCM.

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“…HCM mutations in the regulatory light chain (RLC) of myosin are quite rare, but their importance is due to their essential structural and functional role, by supporting the architecture of the myosin neck region and finely regulating the kinetics of the actin-myosin interaction [8]. Another HCM-related gene that is becoming increasingly important is TNNC1, encoding Troponin C; notwithstanding that mutations in this gene represent a relatively rare cause of HCM-cases, recent evidence highlights a correlation between TNNC1 variants and an adverse clinical outcome, in terms of earliest onset of the disease and highest frequency of fatal events [9]. HCM shows a prevalence of 1/500 in the general population [1,2], with a worldwide distribution, as cases have been observed in over 60 countries on all continents [2], and it affects males and females [10] as well as subjects of various ethnic origins, with similar prevalence, clinical course and phenotypic disease expression [2,5,10].…”

Section: Hypertrophic Cardiomyopathy: a Brief Overview Identifying Sudden Cardiac Death As The Principal Clinical Burden Of The Diseasementioning

confidence: 99%

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

Santini

Coppini

Cerbai

2021

Cells

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Life-threatening ventricular arrhythmias are the main clinical burden in patients with hypertrophic cardiomyopathy (HCM), and frequently occur in young patients with mild structural disease. While massive hypertrophy, fibrosis and microvascular ischemia are the main mechanisms underlying sustained reentry-based ventricular arrhythmias in advanced HCM, cardiomyocyte-based functional arrhythmogenic mechanisms are likely prevalent at earlier stages of the disease. In this review, we will describe studies conducted in human surgical samples from HCM patients, transgenic animal models and human cultured cell lines derived from induced pluripotent stem cells. Current pieces of evidence concur to attribute the increased risk of ventricular arrhythmias in early HCM to different cellular mechanisms. The increase of late sodium current and L-type calcium current is an early observation in HCM, which follows post-translation channel modifications and increases the occurrence of early and delayed afterdepolarizations. Increased myofilament Ca2+ sensitivity, commonly observed in HCM, may promote afterdepolarizations and reentry arrhythmias with direct mechanisms. Decrease of K+-currents due to transcriptional regulation occurs in the advanced disease and contributes to reducing the repolarization-reserve and increasing the early afterdepolarizations (EADs). The presented evidence supports the idea that patients with early-stage HCM should be considered and managed as subjects with an acquired channelopathy rather than with a structural cardiac disease.

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Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes

Cited by 36 publications

References 57 publications

Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy

Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy

Genetic Restrictive Cardiomyopathy: Causes and Consequences—An Integrative Approach

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

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