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

AbstractIn 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 inMYBPC3.
Source: Journal of Cardiovascular Translational Research - Category: Cardiology Source Type: research

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Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease. Although the genetic cause of HCM has been linked to mutations in genes encoding sarcomeric proteins, the ability to predict clinical outcomes based on specific mutations in HCM patients is limited. Moreover, how mutations in different sarcomeric proteins can result...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: Physical Sciences Source Type: research
AbstractAimsAmyloid cardiomyopathy is an underappreciated cause of morbidity and mortality. Recent evidence suggests that ATTR wild ‐type cardiomyopathy (ATTRwt‐CM) is probably much more common than widely appreciated. So far, no data are available on comparison of mortality from ATTRwt‐CM and other heart failure aetiologies.Methods and resultsThis was a retrospective, observational, cohort study of 2251 patients and their data collected prospectively from May 2000 to June 2018. Long ‐term mortality was the main outcome measure. Underlying cardiomyopathies were classified as amyloid CM (6.1%) [ATTRwt 3.0%; light‐...
Source: ESC Heart Failure - Category: Cardiology Authors: Tags: Original Research Article Source Type: research
AbstractTraditionally thought of primarily as the predominant regulator of myocardial perfusion, it is becoming more accepted that the human coronary microvasculature also exerts a more direct influence on the surrounding myocardium. Coronary microvascular dysfunction (CMD), not only precedes large artery atherosclerosis, but is associated with other cardiovascular diseases such as heart failure with preserved ejection fraction (HFpEF) and hypertrophic cardiomyopathy (HCM). It is also highly predictive of cardiovascular events in patients with or without atherosclerotic cardiovascular disease. This review focuses on this r...
Source: Microcirculation - Category: Research Authors: Tags: INVITED REVIEWS Source Type: research
As the most metabolically demanding organ in the body, the heart must generate massive amounts of energy adenosine triphosphate (ATP) from the oxidation of fatty acids, carbohydrates and other fuels (e.g., amino acids, ketone bodies), in order to sustain constant contractile function. While the healthy mature heart acts omnivorously and is highly flexible in its ability to utilize the numerous fuel sources delivered to it through its coronary circulation, the heart’s ability to produce ATP from these fuel sources becomes perturbed in numerous cardiovascular disorders. This includes ischemic heart disease and myocardi...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
A 30-something was in the ED for some minor trauma when he was noted to have a fast heart rate.  He acknowledged that he had palpitations. but only when asked.  He had a history heavy alcohol use.  Blood pressure was normal (109/83).Here is his 12-lead:There is a wide complex tachycardia with a rate of 257, with RBBB and LPFB (right axis deviation) morphology.The Differential Diagnosis is: SVT with aberrancy(#)     [AVNRT vs. WPW (also called AVRT*)]    Atrial flutter with 1:1 conduction, with aberrancy    VT coming from the anterior fascicle (fascicular...
Source: Dr. Smith's ECG Blog - Category: Cardiology Authors: Source Type: blogs
ConclusionsIn our single ‐centre experience, the majority of patients with chronic HFrEF treated with beta‐blocker therapy did not achieve target doses over time, and a substantial proportion had inadequate control of resting HR. There was no relationship between achieved beta‐blocker target dose and resting HR contro l.
Source: ESC Heart Failure - Category: Cardiology Authors: Tags: Original Research Article Source Type: research
We present 7 children with congenital heart disease and coronavirus disease 2019. Of these, 5 were younger than 1  year of age and 3 had atrioventricular canal defect and trisomy 21. All 7 developed acute decompensation, with 1 death in an 18-year-old with hypertrophic cardiomyopathy and other comorbidities.
Source: The Journal of Pediatrics - Category: Pediatrics Authors: Tags: Brief Reports Source Type: research
We present 7 children with congenital heart disease and coronavirus disease 2019. Of these, 5 were younger than 1  year of age and 3 had atrioventricular canal defect and trisomy 21. All 7 developed acute decompensation, with 1 death in an 18-year-old with hypertrophic cardiomyopathy and other comorbidities.
Source: The Journal of Pediatrics - Category: Pediatrics Authors: Tags: Brief Reports Source Type: research
We present seven children with congenital heart disease and coronavirus disease-2019. Of these, five were under one-year-of-age and three had atrioventricular canal defect and trisomy 21. All seven developed acute decompensation, with one death in an 18-year-old with hypertrophic cardiomyopathy and other co-morbidities.
Source: The Journal of Pediatrics - Category: Pediatrics Authors: Tags: Brief Reports Source Type: research
Abstract BACKGROUND: Chronic valvular heart disease leads to systolic dysfunction and left atrial enlargement that ultimately results in heart failure. PURPOSE: To investigate prognostic importance of Echocardiography and plasma natriuretic peptide levels that increase as a compensatory response and can be used as predictive markers for cardiac hypertrophy. MATERIAL AND METHODS: The patients were divided into three groups: 51 with left ventricle hypertrophy due to aortic valve disease; 126 with left atrial enlargement due to mitral valve dysfunction; and 76 with both conditions. Atrial natriuretic peptid...
Source: Acta Radiologica - Category: Radiology Authors: Tags: Acta Radiol Source Type: research
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