Association of 25 bp Deletion in MYBPC3 Gene with Left Ventricle Dysfunction in Coronary Artery Disease Patients

Srivastava, Anshika; Garg, Naveen; Mittal, Tulika; Khanna, Roopali; Gupta, Shipra; Seth, Prahlad K.; Mittal, Balraj

doi:10.1371/journal.pone.0024123

Cited by 23 publications

(17 citation statements)

References 30 publications

(42 reference statements)

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“…The true prevalence throughout South Asia has been estimated to be lower, but larger population samples are likely needed (Simonson et al, 2010). This deletion has also been linked to increased left ventricular dysfunction after myocardial infarction (Srivastava et al, 2011) consistent with this variant increasing susceptibility to heart failure, especially in combination with other cardiac insults. Rare instances of individuals with two mutant alleles of MYBPC3 and early onset lethal disease have been described, and often associate with the feature of noncompaction (Dellefave et al, 2009; Lekanne Deprez et al, 2006; Schaefer et al, 2014; Wessels et al, 2014).…”

Section: Hypertrophic Cardiomyopathy and Thick Filament Gene Mutationsmentioning

confidence: 89%

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

2015

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Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output. Dilated cardiomyopathy is often triggered by mutations that disrupt the giant protein titin. The energetic consequences of these mutations offer molecular targets and opportunities for new drug development and gene correction therapies.

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Section: Hypertrophic Cardiomyopathy and Thick Filament Gene Mutationsmentioning

confidence: 89%

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

2015

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“…[32] Additionally, Additionally, MYBPC3 variants have been associated with impaired ventricular function in patients with coronary artery disease. [33] However, it is not clear why ventricular function is less impaired in patients with MYH7 variants since an interaction between the two genes seems to be necessary to maintain systolic function. [34] There was also a trend towards increased LGE burden in patients with MYBPC3 variants, which itself was associated with an increase in sustained VT or ICD shock.…”

Section: Phenotype In Patients With Genetic Variantsmentioning

confidence: 99%

Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging

et al. 2019

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HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing. Methods Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death. Results We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020).

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“…Carrying the mutation leads to increased susceptibility to worse outcome following cardiac disease. For example, patients with coronary artery disease also carrying the deletion had significantly worse systolic function [43]. …”

Section: A Highly Prevalent C-terminal Mutation In Cmybp-cmentioning

confidence: 99%

MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation

Kuster

Sadayappan

2013

Pflugers Arch - Eur J Physiol

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Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. HCM is caused by mutations in genes encoding contractile proteins. Cardiac myosin binding protein-C (cMyBP-C) is a thick filament contractile protein that regulates sarcomere organization and cardiac contractility. About 200 different mutations in the cMyBP-C gene (MYBPC3) have thus far been reported as causing HCM. Among them, a 25 base pair deletion in the branch point of intron 32 of MYBPC3 is widespread, particularly in South Asia, where it affects ≈4% of South Asian descendants worldwide. This polymorphic mutation results in skipping of exon 33 and a reading frame shift, which, in turn, replaces the last 65 amino acids of the C-terminal C10 domain of cMyBP-C (cMyBP-CC10mut) with a novel sequence of 58 residues. Carriers of the 25 base pair deletion mutation are at increased risk of developing cardiomyopathy and heart failure. Because of the high prevalence of this mutation in certain populations, genetic screening of at-risk groups might be beneficial. Scientifically, the functional consequences of C-terminal mutations and the precise mechanisms leading to HCM should be defined using induced pluripotent stem cells and engineered heart tissue in vitro, or mouse models in vivo. Most importantly, therapeutic strategies that include pharmacology, gene repair and gene therapy should be developed to prevent the adverse clinical effects of cMyBP-CC10mut. This review article aims to examine the effects of cMyBP-CC10mut on cardiac function, emphasizing the need for the development of genetic testing and expanded therapeutic strategies.

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Association of 25 bp Deletion in MYBPC3 Gene with Left Ventricle Dysfunction in Coronary Artery Disease Patients

Cited by 23 publications

References 30 publications

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure

Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging

MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation

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