Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy

Rafael, Julianny Freitas; Filho, Fernando Eugênio dos Santos Cruz; Carvalho, Antônio Carlos Campos de; Gottlieb, Ilan; Cazelli, José Guilherme; Siciliano, Ana Paula dos Reis Velloso; Dias, Glauber Monteiro

doi:10.5935/abc.20170045

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…Bioinformatics predictions did not suggest loss of natural splice sites. Indeed, all five algorithms did not show any probability of canonical splice site loss compared to a well-established pathogenic mutation c.1624G>C (p.E542Q) of MYBPC3 27,48 (Figure 1, B). Similar results were obtained for the prediction of activation of cryptic splicing sites (data not shown).…”

Section: C1809t>g (Pi603m) Does Not Induce Alterations In Rna Splicingmentioning

confidence: 93%

Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C

Pricolo

Herrero-Galán

Mazzaccara

et al. 2020

J. of Cardiovasc. Trans. Res.

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In the era of Next Generation Sequencing (NGS), genetic testing for inherited disorders identifies an ever-increasing number of variants whose pathogenicity remains unclear. These variants of uncertain significance (VUS) limit the reach of genetic testing in clinical practice. The VUS for Hypertrophic Cardiomyopathy (HCM), the most common familial heart disease, constitute over 60% of entries for missense variants shown in ClinVar database. We have studied a novel VUS (c.1809T>G-p.I603M) in the most frequently mutated gene in HCM, MYBPC3, which codes for cardiac myosin-binding protein C (cMyBPC). Our determinations of pathogenicity integrate bioinformatics evaluation and functional studies of RNA splicing and protein thermodynamic stability. In silico prediction and mRNA analysis indicated no alteration of RNA splicing induced by the variant. At the protein level, the p.I603M mutation maps to the C4 domain of cMyBPC. Although the mutation does not perturb much the overall structure of the C4 domain, the stability of C4 I603M is severely compromised as detected by circular dichroism and differential scanning calorimetry experiments. Taking into account the highly destabilizing effect of the mutation in the structure of C4, we propose reclassification of variant p.I603M as likely pathogenic. Looking into the future, the workflow described here can be used to refine the assignment of pathogenicity of variants of uncertain significance in MYBPC3.

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Section: C1809t>g (Pi603m) Does Not Induce Alterations In Rna Splicingmentioning

confidence: 93%

Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C

Pricolo

Herrero-Galán

Mazzaccara

et al. 2020

J. of Cardiovasc. Trans. Res.

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“…Several genetic studies have found an association between LVD and dilated cardiomyopathy (DCM). Various sarcomeric protein-encoding genes such as cardiac myosin-binding protein C (MYBPC3), myosin heavy polypeptide, and cardiac troponin I gene mutations, as well as other gene mutations have been identified in DCM [7][8][9][10][11][12][13]. The common sarcomeric gene polymorphisms with their locations and functional roles are given in Table 1.…”

Section: Common Sarcomeric Protein and Associated Gene Polymorphismmentioning

confidence: 99%

Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease

Kumar

Kim

2020

Biomolecules

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Cardiovascular diseases are one of the leading causes of death in developing countries, generally originating as coronary artery disease (CAD) or hypertension. In later stages, many CAD patients develop left ventricle dysfunction (LVD). Left ventricular ejection fraction (LVEF) is the most prevalent prognostic factor in CAD patients. LVD is a complex multifactorial condition in which the left ventricle of the heart becomes functionally impaired. Various genetic studies have correlated LVD with dilated cardiomyopathy (DCM). In recent years, enormous progress has been made in identifying the genetic causes of cardiac diseases, which has further led to a greater understanding of molecular mechanisms underlying each disease. This progress has increased the probability of establishing a specific genetic diagnosis, and thus providing new opportunities for practitioners, patients, and families to utilize this genetic information. A large number of mutations in sarcomeric genes have been discovered in cardiomyopathies. In this review, we will explore the role of the sarcomeric genes in LVD in CAD patients, which is a major cause of cardiac failure and results in heart failure.

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“…It usually occurs with the rule of familial autosomal dominant inheritance and with genetic heterogeneity. 1 , 2 In general population, its incidence rate is 0.23%, and the annual mortality rate is about 1% to 2%. 3 , 4 In patients with HCM, myocardial tissue is hypertrophy below the level of the left ventricular papillary muscle at the apex, and this hypertrophy is abnormal and asymmetric.…”

Section: Introductionmentioning

confidence: 99%

Angiotensinogen M235T polymorphism and susceptibility to hypertrophic cardiomyopathy in Asian population: A meta analysis

Zhen

Wang

Chen

et al. 2020

J Renin Angiotensin Aldosterone Syst

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Objective: To explore the relationship between the polymorphism of angiotensinogen gene (AGT) M235T and susceptibility to hypertrophic cardiomyopathy (HCM) in Asian population by meta-analysis. Methods: PubMed, Embase, Web of Science, Cochrane library, CNKI, Wan Fang, and other databases were searched to collect the literature about AGT M235T polymorphism and HCM from the inception to March 1, 2020. The Newcastle-Ottawa Scale (NOS) checklist was uesd to perform independent literature review and study quality assessment. Data was analyzed by Stata 15.0 software. Results: The results showed that, except for the recessive genetic model (TT vs MT+MM: OR = 1.27, 95%CI: 1.05–1.53), in the other four genetic models, the M235T polymorphism had no significant correlation with the risk of HCM (T vs M: OR = 1.17, 95%CI: 0.88–1.57; TT+MT vs MM: OR = 1.13, 95%CI: 0.55–2.33; TT vs MM: OR = 1.25, 95%CI: 0.60–2.59; TM vs MM: OR = 0.95, 95%CI0.5–1.82). The results of subgroup analysis showed that, except for the heterozygous genetic model, in the other four genetic models, M235T polymorphism was significantly associated with sporadic hypertrophic cardiomyopathy (SHCM), but not with familial hypertrophic cardiomyopathy (FHCM) ( p > 0.05). Conclusion: M235T polymorphism in Asians is associated with HCM, especially SHCM. Heterozygotes increase the risk of patients with SHCM.

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Myosin-binding Protein C Compound Heterozygous Variant Effect on the Phenotypic Expression of Hypertrophic Cardiomyopathy

Cited by 5 publications

References 24 publications

Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C

Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C

Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease

Angiotensinogen M235T polymorphism and susceptibility to hypertrophic cardiomyopathy in Asian population: A meta analysis

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