Homozygous missense <i>MYBPC3</i> Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy

Kissopoulou, Antheia; Trinks, Cecilia; Gréen, Anna; Karlsson, Jan‐Erik; Jonasson, Jon; Gunnarsson, Cecilia

doi:10.1002/ehf2.12288

Cited by 10 publications

(4 citation statements)

References 20 publications

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“…MYBPC3 mutations present a high risk for HF [ 84 ]. Kissopoulou et al (2018) showed that homozygous missense MYBPC3 Pro873His mutation in human HCM is associated with an increased risk of HF development [ 85 ]. Chronic administration of β-adrenergic agonists, such as isoproterenol, has been shown to aggravate HCM and induce HF in HCM models of disease [ 86 ].…”

Section: Discussionmentioning

confidence: 99%

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Glavaški

Velicki

2021

Life

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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with a prevalence of 1 in 500 people and varying clinical presentations. Although there is much research on HCM, underlying molecular mechanisms are poorly understood, and research on the molecular mechanisms of its specific clinical presentations is scarce. Our aim was to explore the molecular mechanisms shared by HCM and its clinical presentations through the automated extraction of molecular mechanisms. Molecular mechanisms were congregated by a query of the INDRA database, which aggregates knowledge from pathway databases and combines it with molecular mechanisms extracted from abstracts and open-access full articles by multiple machine-reading systems. The molecular mechanisms were extracted from 230,072 articles on HCM and 19 HCM clinical presentations, and their intersections were found. Shared molecular mechanisms of HCM and its clinical presentations were represented as networks; the most important elements in the intersections’ networks were found, centrality scores for each element of each network calculated, networks with reduced level of noise generated, and cooperatively working elements detected in each intersection network. The identified shared molecular mechanisms represent possible mechanisms underlying different HCM clinical presentations. Applied methodology produced results consistent with the information in the scientific literature.

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Section: Discussionmentioning

confidence: 99%

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Glavaški

Velicki

2021

Life

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“…There is no large randomized study regarding the natural course of HCM in patients carrying more than one pathogenic or likely pathogenic allele. However, many particular clinical cases, case-control and observational studies have pointed out that the role of a second genetic hit can be crucial in the age of HCM manifestation ( Wessels et al, 2015 ; Dzemeshkevich et al, 2018 ; Kissopoulou et al, 2018 ). Prospective genetic counseling was also challenging.…”

Section: Discussionmentioning

confidence: 99%

Mixed Hypertrophic and Dilated Phenotype of Cardiomyopathy in a Patient With Homozygous In-Frame Deletion in the MyBPC3 Gene Treated as Myocarditis for a Long Time

et al. 2020

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Hypertrophic cardiomyopathy (HCM) is the most common inherited disease, with a prevalence of 1:200 worldwide. The cause of HCM usually presents with an autosomal dominant mutation in the genes encoding one of more than 20 sarcomeric proteins, incomplete penetrance, and variable expressivity. HCM classically manifests as an unexplained thickness of the interventricular septum (IVS) and left ventricular (LV) walls, with or without the obstruction of the LV outflow tract (LVOT), and variable cardiac arrhythmias. Here, we present a rare case of mixed cardiomyopathy (cardiac hypertrophy and dilation) and erythrocytosis in a young patient. A 27-year-old man was admitted to the clinic due to biventricular heart failure (HF) NYHA class III. Personal medical records included a diagnosis of dilated cardiomyopathy (DCM) since the age of 4 years and were, at the time, considered an outcome of myocarditis. Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis. The combination of non-obstructive LV hypertrophy (LV walls up to 15 mm), LV dilatation, decreased contractility (LV EF 24%), and LV apical thrombosis were seen. Cardiac MRI showed a complex pattern of late gadolinium enhancement (LGE). Endomyocardial biopsy (EMB) revealed primary cardiomyopathy with intravascular coagulation and an inflammatory response. No viral genome was detected in the plasma or EMB samples. Whole exome sequencing (WES) revealed a homozygous in-frame deletion p.2711_2737del in the MyBPC3 gene. The clinically unaffected mother was a heterozygous carrier of this deletion, and the father was unavailable for clinical and genetic testing. Essential erythrocytosis remains unexplained. No significant improvement was achieved by conventional treatment, including prednisolone 40 mg therapy. ICD was implanted due to sustained VT and high risk of SCD. Orthotopic heart transplantation (HTx) was considered optimal. Early manifestation combined hypertrophic and dilated phenotype, and progression may reflect a complex genotype with more than one pathogenic allele and/or a combination of genetic diseases in one patient.

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“…The presence of bi-allelic truncating MYBPC3 mutations in patients is linked to neonatal cardiomyopathy, and can result in heart failure and mortality within the first year of life. These findings suggest that a gene-dosage effect could be responsible for the manifestation of the disease at younger ages [ 78 , 79 , 80 ].…”

Section: From Genetics To Clinical Implicationsmentioning

confidence: 99%

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

Tudurachi,

Zăvoi,

Leonte

et al. 2023

IJMS

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Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM’s morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin–proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM.

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Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy

Cited by 10 publications

References 20 publications

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Shared Molecular Mechanisms of Hypertrophic Cardiomyopathy and Its Clinical Presentations: Automated Molecular Mechanisms Extraction Approach

Mixed Hypertrophic and Dilated Phenotype of Cardiomyopathy in a Patient With Homozygous In-Frame Deletion in the MyBPC3 Gene Treated as Myocarditis for a Long Time

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

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