Search Results (83)

Introduction: Cardiomyopathies (DCM, HCM, and ACM) and primary arrhythmogenic disorders (BrS, LQTS, and CPVT) represent the most common causes of sudden cardiac death (SCD) in young individuals. Systematic genome-wide single-nucleotide polymorphism (SNP) analyses and genome-wide association studies (GWASs) have enabled the identification of numerous genetic variants associated with cardiovascular diseases. Body: Genetic testing for cardiomyopathies and inherited channelopathies primarily involves panel testing of genes with definitive and strong evidence of disease association; genes supported by moderate evidence may also be considered. Cardiomyocytes express a variety of proteins implicated in the pathogenesis of genetic cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal, and nuclear envelope proteins. Inherited cardiac channelopathies result from mutations in genes encoding cellular components that influence calcium ion availability or affect membrane ion channels, including sodium, potassium, and calcium channels. Common variants associated with SCD are found in genes encoding cardiac ion channels (e.g., SCN5A, KCNQ1, and KCNH2), calmodulin (CALM2), sarcomeric proteins (MYH7, MYBPC3, TTN, and TNNI3), and desmosomal proteins (RyR2 and DES). Conclusions: This review demonstrates that specific genetic variants are significantly associated with an increased risk of SCD. The evidence underscores the importance of genetic screening and early intervention in individuals with a family history of SCD or other risk factors for inherited cardiac disorders predisposing to SCD. Future research should focus on gene-specific management strategies for familial cardiomyopathies and inherited channelopathies, with the goal of improving targeted genetic therapies and reducing the burden of sudden cardiac death. Full article

Hypertrophic cardiomyopathies (HCMs) are among the most common genetic disorders; however, they might be underdiagnosed. Sequencing core sarcomere gene panels remain the main diagnostic tool. We present the results of HCM genetic testing performed at Lithuania’s tertiary care center. All patients with diagnosed or clinically suspected HCM underwent next-generation panel sequencing. Of 204 patients, 34 (16.7%) received a genetic diagnosis. The most commonly affected genes were MYBPC3 and MYH7. Notably, two patients were found to have LEOPARD syndrome due to PTPN11 gene variants. Our results indicate that patients with an identified pathogenic variant were diagnosed with HCM at a younger age and exhibited a more severe phenotype (greater septal wall thickness), although no clear correlation with family history was observed. In addition, four novel MYBPC3 variants, c.3467dup, c.1503C>G, c.2610dup, and c.1251del, were identified. Full article

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an RNA-binding protein known to play critical roles in metabolism, cell proliferation, and tumorigenesis. Although its involvement in muscle development has been documented in several species, the function of goose IGF2BP2 remains largely unexplored. In this study, we cloned and characterized the full-length cDNA and genomic DNA sequences of goose IGF2BP2. The cDNA is 2957 bp in length and contains a 1662 bp open reading frame encoding a 553-amino acid protein with five conserved RNA-binding domains. The genomic sequence spans 12,183 bp and consists of 12 exons and 11 introns. A total of 60 genetic variants were identified, including a deletion of a G base at position 2299 (g.2299delG) that results in a frameshift mutation. Expression analysis revealed high levels of IGF2BP2 mRNA in the liver, heart, and muscle tissues of female geese across embryonic (E25d), growing (A70d), and laying (L270d) stages, consistent with a potential role in muscle development (p < 0.05). Functionally, overexpression of IGF2BP2 in skeletal muscle satellite cells (SMSCs) was associated with significant changes in the expression of several genes linked to muscle development and signaling pathways, including upregulation of IGF1, EGFR, FGF19, BMP6, BMP2, ACVR1C and WNT5A and downregulation of MYBPC3, NODAL, HOXD13, TNXB, and ADD2 (Padj < 0.01). Furthermore, protein–protein interaction (PPI) network analysis of these genes suggests that IGF2BP2 may coordinate key genes, contributing to its potential role in skeletal muscle development in geese. Full article

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in LAMP2 (3) in females, ALPK3homo (1), MYH7 (1), MYBPC3 (1), a heterozygous missense variant in TRIM63 (1), FLNCtv (1), TTNtv (2). For the latter two, electrophoretic analysis of titin isoform composition and protein content in myocardial fragments from explanted hearts confirmed the functional significance of TTN gene variants. The restrictive phenotype in the adult group was associated with carriage of multiple pathogenic sarcomere gene variants: MYL3homo (1), MYBPC3+TPM1 (1), an MYH7 converter domain variant (1), and, in one child, with a TNNT2 variant. This findings support HCM progressing to HT is characterized by a higher frequency of variants in non-sarcomeric genes and Danon disease compared to the general HCM cohort. Full article

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as SCN5A for Brugada syndrome, and MYH7 and MYBPC3 for hypertrophic cardiomyopathy, which have revolutionized diagnosis, risk stratification, and medical management. Nonetheless, issues such as variable expressivity and penetrance, low yield of genetic testing, and relative lack of disease-modifying therapies remain significant hurdles for clinical management. The revolution of genome-wide association studies GWASs has transformed our understanding of inherited arrhythmias and cardiomyopathies, shifting the view of these disorders from a monogenic Mendelian inheritance towards a more complex, often polygenic inheritance with nuanced interplay between genetics and environment. Moreover, GWASs have enabled the quantification of polygenic predisposition to disease using polygenic risk scores, which are often complementary to and independent of monogenic risk. In this review, we highlight how GWASs have transformed the field of inherited arrhythmias and cardiomyopathies, with a particular focus on the polygenic risk scores developed and their clinical utility for the four disorders which have been impacted by GWASs—hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome. Full article

This study examines pediatric cardiomyopathies by analyzing genetic and clinical data from 55 patients (2021–2024) at Beijing Anzhen Hospital. Four subtypes were studied: dilated (DCM, 24), hypertrophic (HCM, 22), arrhythmogenic right ventricular (ARVC, 7), and restrictive (RCM, 2). Clinical data, imaging, labs, and family histories were collected, with whole-exome sequencing (WES) identifying disease-causing variants classified via ACMG guidelines. Statistical analysis revealed a median age of 11 years, a proportion of 58% male participants, and ethnic diversity (21 northern Han, 29 southern Han, 5 minorities). In the cohort, 13 cases had an LVEF below 35%. Pathogenic/likely pathogenic (P/LP) variants were found in 21.8% of the patients, and variants of uncertain significance (VUS) were present in 38.2%, with MYH7 (seven cases) and MYBPC3 (five) being the most common. The WES positivity rates varied, at 58.3% (DCM), 72.7% (HCM), and 33.3% (ARVC/RCM). DCM patients with P/LP/VUS variants showed better contractile function (Fractional Shortening: 29.0% vs. 16.5%, p = 0.008). Females in the DCM group had poorer cardiac function (lower LVEF, higher LVESd, lower cardiac output) compared to males, with more females (nine vs. three) exhibiting an LVEF < 35% (p = 0.041). No significant gender differences were observed in the HCM cases. These findings highlight genotype–phenotype correlations and underscore the need for early intervention in female DCM patients. Full article

Background: Functional single ventricle (FSV) comprises a heterogeneous group of congenital heart diseases (CHDs) with severe and complex abnormalities. The multifactorial etiology of the disease poses challenges in identifying specific pathogenic factors and planning effective interventions and preventive treatments for patients. Methods: Whole-exome sequencing (WES) was performed to identify variants in relevant genes in 29 FSV patients from different families. Results: In total, 95 heterozygous variants across 48 CHD-associated genes were identified, including 85 missense, four small indel, one splicing, one stop gain, and four synonymous variants. Among them, 22 were novels, 11 conflicting, and four pathogenic variants. Each patient carried from two to six variants in different genes, including at least one variant in genes associated with serious heart defects such as AXIN1, BMP2, COL6A2, GATA4, GATA5, GDF1, MESP1, MYH6, NFATC1, NKX2-6, NOTCH1, PCSK9, TBX1, TBX18, and TBX20. In addition, the variants in the COL6A1, CREBBP, DOCK6, EOGT, EP300, LRP2, MYBPC3, MYH7, SEMA3C, and ZFPM2 genes are associated with characteristic phenotypes of FSV, such as atrial septal defect, ventricular septal defect, small left heart syndrome, transposition of the great arteries, and double outlet right ventricle occurring at high frequency in patients. The prediction results suggest that these are potentially pathogenic variants in patients and may explain the phenotype in patients. Conclusions: This is the first study to identify variants associated with functional single ventricle, a complex form of congenital heart disease. Our results contribute to a general understanding of the causes of the disease, thereby guiding treatment and prevention approaches for patients. Full article

Left ventricular hypertrophy (LVH) refers to the pathological thickening of the myocardial wall and is strongly associated with several adverse cardiac outcomes and sudden cardiac death. While the biomechanical drivers of LVH are well established, growing evidence points to a critical role for cardiac and systemic metabolism in modulating hypertrophic remodeling and disease pathogenesis. Despite the efficiency of fatty acid oxidation (FAO), LVH hearts preferentially increase glucose uptake and catabolism to drive glycolysis and oxidative phosphorylation (OXPHOS). The development of therapies to increase and enhance LFCA FAO is underway, with promising results. However, the mechanisms of systemic metabolic states and LCFA dynamics in the context of cardiac hypertrophy remain incompletely understood. Further, it is unknown to what extent cardiac metabolism is influenced by whole-body energy balance and lipid profiles, despite the common occurrence of lipotoxicity in LVH. In this study, we measured whole-body and cellular respiration along with analysis of lipid and glycogen stores in a mouse model of LVH. We found that loss of the cardiac-specific gene, myosin-binding protein C3 (Mybpc3), resulted in depletion of adipose tissue, decreased mitochondrial function in skeletal muscle, increased lipid accumulation in both the heart and liver, and loss of whole-body metabolic flux. We found that supplementation of exogenous LCFAs boosted LVH mitochondrial function and reversed cardiac lipid accumulation but did not fully reverse the hypertrophied heart nor systemic metabolic phenotypes. This study indicates that the LVH phenotype caused systemic metabolic rewiring in Mybpc3^−/− mice and that exogenous LCFA supplementation boosted mitochondrial function in both cardiac and skeletal muscle. Full article

The inclusion of meat quality traits in breeding programs is a promising strategy to improve beef by selecting animals based on both growth and meat quality. This study aimed to estimate genetic parameters for average daily gain (ADG) and Warner–Bratzler shear force (WBSF), as well as to perform genome-wide association studies (GWAS) to identify genomic regions and transcription factor (TF) binding sites associated with both traits in Nelore cattle. Genetic parameters were estimated using a bi-trait Bayesian model, and GWAS identified key SNPs explaining over 1% of variance in genomic estimated breeding values. Candidate genes near these SNPs were annotated, TF binding sites predicted, and gene–TF networks constructed. Genetic estimates indicated moderate heritability for ADG, low heritability for WBSF, and a small negative genetic correlation between traits. Genomic regions contained 116 and 151 candidate genes for ADG and WBSF, respectively, with 35 shared between traits. Functional analyses highlighted MYBPC1 and PENK for WBSF, and GHRS and NPY for ADG. TF analysis identified 25 TFs, with 3 key ones highlighted. Gene–TF networks revealed candidates including CAPN1 and LTBP3 for WBSF, and CARM1 and GH1 for ADG. Shared candidate genes identified in the combined network provide valuable insights into the genetic architecture of growth and tenderness in Nelore cattle. Full article

Muscle traits are critical determinants of meat quality and productivity in sheep, influenced by both breed and anatomical region. Hanzhong sheep, an indigenous Chinese breed, are prized for tender, low-odor meat; yet, the molecular mechanisms underlying these traits remain poorly understood. In this study, we integrated meat quality assessment with metabolomic and transcriptomic profiling of the longissimus dorsi (HZ-B) and triceps brachii (HZ-T) muscles to elucidate biochemical and molecular bases of regional differences. The results, derived from metabolomic profiling, demonstrated that the muscle tissue of Hanzhong sheep contained abundant proteins (95 kinds) and fatty acids (150 kinds). The greater tenderness of HZ-B compared to HZ-T was associated with higher levels of dipeptides such as carnosine (FC = 1.07) and anserine (FC = 1.04), as well as upregulated expression of oxidative fiber-related genes MYH2 (FC = 2.92) and TPM1 (FC = 2.15). In contrast, HZ-T showed enrichment of flavor-associated metabolites, including acylcarnitines and glutamate, alongside higher expression of FBXO32 (FC = 0.35) and MYBPC1 (FC = 0.47), linked to structural integrity and muscle contraction. Integrated analysis revealed strong associations between metabolite abundance (carnosine/anserine) and key genes (FBXO32/GADL1), suggesting coordinated regulation of meat quality traits. These findings provide mechanistic insights into the metabolic and transcriptomic determinants of muscle quality in Hanzhong sheep, offering a foundation for genetic improvement and conservation strategies. Full article

Protein association and aggregation are fundamental processes that play critical roles in a variety of biological phenomena from cell signaling to the development of incurable diseases, including amyloidoses. Understanding the basic biophysical principles governing protein aggregation processes is of crucial importance for developing treatment strategies for diseases associated with protein aggregation, including sarcopenia, as well as for the treatment of pathological processes associated with the disruption of functional protein complexes. This work, using a set of methods such as atomic force microscopy (AFM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction, as well as bioinformatics analysis, investigated the structures of complexes formed by titin and myosin-binding protein C (MyBP-C). TEM revealed the formation of morphologically ordered aggregates in the form of beads during co-incubation of titin and MyBP-C under close-to-physiological conditions (175 mM KCl, pH 7.0). AFM showed the formation of a relatively homogeneous film with local areas of relief change. Fluorimetry with thioflavin T, as well as FTIR spectroscopy, revealed signs of an amyloid-like structure, including a signal in the cross-β region. X-ray diffraction showed the presence of a cross-β structure characteristic of amyloid aggregates. Such structural features were not observed in the control samples of the investigated proteins separately. In sarcomeres, these proteins are associated with each other, and this interaction plays a partial role in the formation of a strong sarcomeric cytoskeleton. We found that under physiological ionic-strength conditions titin and MyBP-C form complexes in which an amyloid-like structure is present. The possible functional significance of amyloid-like aggregation of these proteins in muscle cells in vivo is discussed. Full article

This review aims to provide a comprehensive framework for implementing precision sports medicine, integrating genetics, pharmacogenomics, digital health solutions, and multi-omics data. Literature review was conducted using MEDLINE, EMBASE, Web of Science, and Cochrane Library databases (January 2018–April 2024), focusing on precision medicine applications in sports medicine, utilizing key terms including “precision medicine”, “sports medicine”, “genetics”, and “multi-omics”, with forward and backward citation tracking. The review identified key gene variants affecting athletic performance: endurance (AMPD1, PPARGC1A), power (ACTN3, NOS3), strength (PPARG), and injury susceptibility (COL5A1, MMP3), while also examining inherited conditions like cardiomyopathies (MYH7, MYBPC3). Pharmacogenomic guidelines were established for optimizing common sports medications, including NSAIDs (CYP2C9), opioids (CYP2D6), and cardiovascular drugs (SLCO1B1, CYP2C19). Digital health technologies, including wearables and predictive analytics, showed potential for enhanced athlete monitoring and injury prevention, while multi-omics approaches integrated various molecular data to understand exercise capacity and injury predisposition, enabling personalized assessments, training regimens, and therapeutic interventions based on individual biomolecular profiles. This review provides sports medicine professionals with a framework to deliver personalized care tailored to each athlete’s unique profile, promising optimized performance, reduced injury risks, and improved recovery outcomes. Full article

Myosin-binding protein C (MyBP-C) comprises a family of myofilament proteins that maintain sarcomeric structure and regulate actomyosin crossbridge cycling. Pathogenic variants in MYBPC1, the gene encoding the slow skeletal isoform (sMyBP-C), lead to a dominant congenital myopathy, termed Myotrem, characterized by muscle weakness, hypotonia, and a distinctive tremor of myogenic origin, in the absence of neuropathy. However, the molecular mechanism(s) of myogenic tremorgenesis is largely unknown. One potential mechanism is aberrant myofilament stretch activation, which is defined as a delayed increase in force after a rapid stretch. We utilized the Myotrem murine model harboring the pathogenic MYBPC1 E248K variant to test the hypothesis that stretch activation is augmented in permeabilized Myotrem E248K soleus fibers. We found that stretch activation was significantly increased in E248K soleus muscle fibers. Interestingly, once submaximally Ca²⁺ activated, a subpopulation of slow-twitch E248K fibers exhibited spontaneous pulsatile sarcomere oscillations. This pulsing behavior generated a sinusoidal waveform pattern in sarcomere length, which often persisted on a timescale of minutes. These results align with sMyBP-C as key regulator of the synchronous activation of myofilaments by dampening both spontaneous oscillatory activity and stretch-dependent activation. We propose that the presence of sMyBP-C-E248K disrupts this regulation, thereby driving pathogenic myogenic tremors. Full article

Background/Objectives: While T₂^* mapping effectively assesses cerebral blood oxygenation, its utility for capturing cardiac phase-dependent myocardial changes in hypertrophic cardiomyopathy (HCM) is underexplored. This study investigates T₂^* dynamics in an HCM mouse model, to validate T₂^* as a clinically relevant biomarker for improved HCM diagnosis and treatment monitoring. Methods: A cardiac-specific Mybpc3 genetic mouse model, closely mirroring human HCM, was used with 12 young mice (6–11 weeks old), including both male and female wild-type (WT) and Mybpc3-KI (HCM) groups. The cardiac function was assessed using self-gated multi-slice 2D CINE imaging. To investigate myocardial T₂^* variations across the cardiac cycle, multi-gradient echo (MGE) imaging was employed. This approach used retrospective gating and continuous acquisition synchronization with pulse oximetry at 9.4 T small animal MRI. Results: Mybpc3-KI mice demonstrated left-ventricular (LV) hypertrophy compared to WT (HCM = 50.08 ± 4.68 µm/g vs. WT = 45.80 ± 20.07 µm/g, p < 0.01) and reduced ejection fraction (HCM = 38.55 ± 5.39% vs. WT= 72.53 ± 3.95%, p < 0.01). Myocardial T₂^* was significantly elevated in HCM across all cardiac phases (HCM = 12.14 ± 1.54 ms vs. WT = 7.93 ± 1.57 ms, p = 0.002). Strong correlations were observed between myocardial T₂^* and LV mass (rho = 0.88, p = 0.03). Conclusions: T₂^* was elevated in HCM with increased LV mass, highlighting the potential of T₂^* MRI as a sensitive biomarker for distinguishing healthy mice from those with HCM and revealing possible myocardial abnormalities. Full article

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder marked by abnormal thickening of the left ventricular myocardium, often leading to arrhythmias and heart failure. Mutations in sarcomeric protein genes, particularly MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), are major contributors to HCM pathogenesis. This study aims to investigate the structural and functional effects of two HCM-associated missense mutations, p.S236G and p.E334K, located within the C0–C2 domains of cMyBP-C. Methods: Following in silico analysis, a bacterial expression system was applied, enabling the discrete C0–C2 domains of wild-type (cMyBP-C^WT) and mutant (cMyBP-C^S236G and cMyBP-C^E334K) cMyBP-C proteins to be expressed and purified as recombinant proteins. Structural and stability changes were assessed using circular dichroism (CD), differential scanning calorimetry (DSC), and chemical denaturation assays. Functional impact on actin binding was also evaluated in vitro. Results: CD analysis revealed altered secondary structure in both mutants compared to the wild-type protein. Thermal and chemical stability assays indicated increased stability in the cMyBP-C^E334K mutant, suggesting that it exhibits a more rigid conformation. This increased rigidity corresponded with a significant reduction in the actin-binding affinity relative to the wild-type protein. Conclusions: Our findings demonstrate specific detrimental effects of the p.E334K mutation and underscore the importance of understanding the structural and functional consequences of HCM-associated mutations to assist the development of targeted therapeutic strategies. Full article