Search Results (45)

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The most frequently mutated genes encode proteins of the thick filament of the sarcomere, while mutations in thin-filament genes are rare findings in HCM cohorts. Recent studies have revealed distinct mechanisms of disease development linked to thin-filament mutations, highlighting the need for further investigation into this rare subgroup. Methods: A total of 82 adult patients with sarcomere-positive HCM were enrolled. Baseline characteristics and nearly five years of follow-up data from 15 patients with thin-filament mutations were analyzed and compared with those from 67 patients with thick-filament mutations and findings from other studies. Results: Compared to thick-filament HCM patients, individuals with thin-filament mutations exhibited significantly lower maximum left ventricular wall thickness, as measured by both echocardiography (p = 0.024) and cardiac magnetic resonance (p = 0.006), showed more rapid progression to advanced heart failure (HR = 5.6, p = 0.018), and less often underwent septal reduction therapy (p = 0.025). None of the thin-filament HCM patients experienced malignant arrhythmic events. Conclusions: In adults, thin-filament HCM is associated with a ‘thinner’ phenotype and a more rapid progression to advanced heart failure compared to thick-filament HCM. Data on a higher risk of malignant arrhythmias in thin-filament HCM remain controversial between studies and rather depend on the age of onset and genotype in each particular family. Full article

Background: Among numerous genes that have been a focus of equine genetic research, the KL (Klotho) and ACTN3 (Alpha-actinin-3) genes stand out due to their significant roles in muscle function and overall health, as well as performance ability. Previous studies on Arabian horses and other mammalians have shown that both KL and ACTN3 occur in different isoforms that seem to have different roles in metabolism. The main purpose of this present study was to describe different isoforms (ACTN3, ACTN3-201, ACTN3-202, KL, KL-202, KL-203) expression levels affected by the endurance effort in Arabian horses. Methods: Blood samples were taken from a group of n = 10 Arabian horses taking part in a long-distance 120 km endurance ride. After RNA isolation and reverse transcription, real-time PCR was performed. The expression levels (Relative Quantity, RQ) were calculated using the delta-delta CT method. The results showed surprisingly large differences between different isoforms expression levels which brought us to the conclusion that both KL and ACTN3 genes are suitable genetic markers to measure endurance performance. Moreover, the correlation network analyses showed that the MIOX (myo-inositol oxygenase), SH3RH2 (SH3 domain-containing ring finger 2) and TNNI2 (Troponin I2, fast skeletal type) genes are significantly involved in the endurance effort metabolism. Full article

The duck industry is vital for supplying high-quality protein, making research into the development of duck skeletal muscle critical for improving meat and egg production. In this study, we leveraged Oxford Nanopore Technologies (ONT) sequencing to perform full-length transcriptome sequencing of myoblasts harvested from the leg muscles of duck embryos at embryonic day 13 (E13), specifically examining both the proliferative (GM) and differentiation (DM) phases. Our analysis identified a total of 5797 novel transcripts along with 2332 long non-coding RNAs (lncRNAs), revealing substantial changes in gene expression linked to muscle development. We detected 3653 differentially expressed genes and 2246 instances of alternative splicing, with key genes involved in essential pathways, such as ECM–receptor interaction and Notch signaling, prominently featured. Additionally, we constructed a protein–protein interaction network that highlighted critical regulators—MYOM3, MYL2, MYL1, TNNI2, and ACTN2—associated with the processes of proliferation and differentiation in myoblasts. This extensive transcriptomic investigation not only sheds light on the intricate molecular mechanisms driving skeletal muscle development in ducks but also provides significant insights for future breeding strategies aimed at enhancing the efficiency of duck production. The results emphasize the efficacy of ONT sequencing in uncovering complex regulatory networks within avian species, ultimately contributing to progress in animal husbandry. Full article

Congenital heart defects (CHDs) rank among the most common birth defects, presenting diverse phenotypes. Genetic and environmental factors are critical in molding the process of cardiogenesis. However, these factors’ interactions are not fully comprehended. Hence, this study aimed to identify and characterize differentially expressed genes involved in CHD development through bioinformatics pipelines. We analyzed experimental datasets available in genomic databases, using transcriptome, gene enrichment, and systems biology strategies. Network analysis based on genetic and phenotypic ontologies revealed that EP300, CALM3, and EGFR genes facilitate rapid information flow, while NOTCH1, TNNI3, and SMAD4 genes are significant mediators within the network. Differential gene expression (DGE) analysis identified 2513 genes across three study types, (1) Tetralogy of Fallot (ToF); (2) Hypoplastic Left Heart Syndrome (HLHS); and (3) Trisomy 21/CHD, with LYVE1, PLA2G2A, and SDR42E1 genes found in three of the six studies. Interaction networks between genes from ontology searches and the DGE analysis were evaluated, revealing interactions in ToF and HLHS groups, but none in Trisomy 21/CHD. Through enrichment analysis, we identified immune response and energy generation as some of the relevant ontologies. This integrative approach revealed genes not previously associated with CHD, along with their interactions and underlying biological processes. Full article

The Tibetan Plateau’s distinctive high-altitude environment, marked by extreme cold and reduced oxygen levels, presents considerable survival challenges for both humans and mammals. Natural selection has led to the accumulation of adaptive mutations in Tibetan pigs, enabling them to develop distinctive adaptive phenotypes. Here, we aim to uncover the genetic mechanisms underlying the adaptation of Tibetan pigs to high-altitude hypoxia. Therefore, we conducted a systematic analysis of 140 whole-genome sequencing (WGS) data points from different representing pig populations. Our analysis identified a total of 27,614,561 mutations, including 22,386,319 single-nucleotide variants (SNVs) and 5,228,242 insertions/deletions (INDELs, size < 50 bp). A total of 11% (2,678,569) of the SNVs were newly identified in our project, significantly expanding the dataset of genetic variants in Tibetan pigs. Compared to other pig breeds, Tibetan pigs are uniquely adapted to high-altitude environments, exhibiting the highest genetic diversity and the lowest inbreeding coefficient. Employing the composite of multiple signals (CMS) method, we scanned the genome-wide Darwinian positive selection signals and identified 32,499 Tibetan pig positively selected SNVs (TBPSSs) and 129 selected genes (TBPSGs), including 213 newly discovered genes. Notably, we identified eight genes (PHACTR1, SFI1, EPM2A, SLC30A7, NKAIN2, TNNI3K, and PLIN2) with strong nature selection signals. They are likely to improve cardiorespiratory function and fat metabolism to help Tibetan pigs become adapted to the high-altitude environment. These findings provide new insights into the genetic mechanisms of high-altitude adaptation and the adaptive phenotypes of Tibetan pigs. Full article

In forensics, one-third of sudden deaths remain unexplained after a forensic autopsy. A majority of these sudden unexplained deaths (SUDs) are considered to be caused by inherited cardiovascular diseases. In this study, we investigated 40 young SUD cases (<40 years), with non-diagnostic structural cardiac abnormalities, using Targeted NGS (next-generation sequencing) for 167 genes previously associated with inherited cardiomyopathies and channelopathies. Fifteen cases identified 17 variants on related genes including the following: AKAP9, CSRP3, GSN, HTRA1, KCNA5, LAMA4, MYBPC3, MYH6, MYLK, RYR2, SCN5A, SCN10A, SLC4A3, TNNI3, TNNI3K, and TNNT2. Of these, eight variants were novel, and nine variants were reported in the ClinVar database. Five were determined to be pathogenic and four were not evaluated. The novel and unevaluated variants were predicted by using in silico tools, which revealed that four novel variants (c.5187_5188dup, p.Arg1730llefsTer4 in the AKAP9 gene; c.1454A>T, p.Lys485Met in the MYH6 gene; c.2535+1G>A in the SLC4A3 gene; and c.10498G>T, p.Asp3500Tyr in the RYR2 gene) were pathogenic and three variants (c.292C>G, p.Arg98Gly in the TNNI3 gene; c.683C>A, p.Pro228His in the KCN5A gene; and c.2275G>A, p.Glu759Lys in the MYBPC3 gene) still need to be further verified experimentally. The results of our study contributed to the general understanding of the causes of SUDs. They provided a scientific basis for screening the risk of sudden death in family members of victims. They also suggested that the Targeted NGS method may be used to identify the pathogenic variants in SUD victims. Full article

Dissecting the genetics of production traits in livestock is of outmost importance, both to understand biological mechanisms underlying those traits and to facilitate the design of selection programs incorporating that information. For the pig industry, traits related to curing are key for protected designation of origin productions. In particular, appropriate ham weight loss after dry-curing ensures high quality of the final product and avoids economic losses. In this study, we analyzed data (N = 410) of ham weight loss after approximately 20 months of dry-curing. The animals used for ham production were purebred pigs belonging to a commercial line. A genome-wide association study (GWAS) of 29,844 SNP markers revealed the polygenic nature of the trait: 221 loci explaining a small percentage of the variance (0.3–1.65%) were identified on almost all Sus scrofa chromosomes. Post-GWAS analyses revealed 32 windows located within regulatory regions and 94 windows located in intronic regions of specific genes. In total, 30 candidate genes encoding receptors and enzymes associated with ham weight loss (MTHFD1L, DUSP8), proteolysis (SPARCL1, MYH8), drip loss (TNNI2), growth (CDCA3, LSP1, CSMD1, AP2A2, TSPAN4), and fat metabolism (AGPAT4, IGF2R, PTDSS2, HRAS, TALDO1, BRSK2, TNNI2, SYT8, GTF2I, GTF2IRD1, LPCAT3, ATN1, GNB3, CMIP, SORCS2, CCSER1, SPP1) were detected. Full article

Skeletal muscle grows in response to a combination of genetic and environmental factors, and its growth and development influence the quality of pork. Elucidating the molecular mechanisms regulating the growth and development of skeletal muscle is of great significance to both animal husbandry and farm management. The Jiangquan black pig is an excellent pig breed based on the original Yimeng black pig, importing the genes of the Duroc pig for meat traits, and cultivated through years of scientific selection and breeding. In this study, full-length transcriptome sequencing was performed on three growth stages of Jiangquan black pigs, aiming to study the developmental changes in Jiangquan black pigs at different developmental stages at the molecular level and to screen the key genes affecting the growth of skeletal muscle in Jiangquan black pigs. We performed an enrichment analysis of genes showing differential expression and constructed a protein–protein interaction network with the aim of identifying core genes involved in the development of Jiangquan black pigs. Notably, genes such as TNNI2, TMOD4, PLDIM3, MYOZ1, and MYH1 may be potential regulators of muscle development in Jiangquan black pigs. Our results contribute to the understanding of the molecular mechanisms of skeletal muscle development in this pig breed, which will facilitate molecular breeding efforts and the development of pig breeds to meet the needs of the livestock industry. Full article

Investigating the causes of Sudden cardiac death (SCD) is always difficult; in fact, genetic cardiac conditions associated with SCD could be “silent” even during autopsy investigation. In these cases, it is important to exclude other aetiology and assist to ask for genetic investigations. Herein, the purpose of this review is to collect the most-implicated genes in SCD and generate a panel with indications for first line and second line investigations. A systematic review of genetic disorders that may cause SCD in the general population was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We subsequently listed the genes that may be tested in the case of sudden cardiac death when the autopsy results are negative or with no evidence of acquired cardiac conditions. To make genetic tests more specific and efficient, it is useful and demanded to corroborate autopsy findings with the molecular investigation as evident in the panel proposed. The genes for first line investigations are HCM, MYBPC3, MYH7, TNNT2, TNNI3, while in case of DCM, the most implicated genes are LMNA and TTN, and in second line for these CDM, ACTN2, TPM1, C1QPB could be investigated. In cases of ACM/ARVC, the molecular investigation includes DSP, DSG2, DSC2, RYR2, PKP2. The channelopathies are associated with the following genes: SCN5A, KCNQ1, KCNH2, KCNE1, RYR2. Our work underlines the importance of genetic tests in forensic medicine and clinical pathology; moreover, it could be helpful not only to assist the pathologists to reach a diagnosis, but also to prevent other cases of SCD in the family of the descendant and to standardise the type of analysis performed in similar cases worldwide. Full article

Sickle cell nephropathy (SCN) is a common complication of sickle cell disease (SCD) that significantly contributes to morbidity and mortality. In addition to clinical and life-style factors, genetic variants influence this risk. We performed a systematic review, searching five databases. Studies evaluating the effect of genetic modifiers on SCN were eligible. Twenty-eight studies (fair-to-good quality) were included: one genome-wide association study, twenty-six case-control studies, and one article combining both approaches. APOL1 was significantly associated with albuminuria and hyperfiltration in children and with worse glomerular filtration in adults. On the other hand, alpha-thalassemia protected patients against albuminuria and hyperfiltration, while BCL11A variants were protective against albuminuria alone. The HMOX1 long GT-tandem repeat polymorphism led to a lower glomerular filtration rate. No modifiers for the risk of hyposthenuria were identified. A genome-wide association approach identified three new loci for proteinuria (CRYL1, VWF, and ADAMTS7) and nine loci were linked with eGFR (PKD1L2, TOR2A, CUBN, AGGF1, CYP4B1, CD163, LRP1B, linc02288, and FPGT-TNNI3K/TNNI3K). In conclusion, this systematic review supports the role of genetic modifiers in influencing the risk and progression of SCN. Incorporating and expanding this knowledge is crucial to improving the management and clinical outcomes of patients at risk. Full article

Mink is a kind of small and precious fur animal resource. In this study, we employed transcriptomics technology to analyze the gene expression profile of mink pectoral muscle tissue, thereby elucidating the regulatory mechanisms underlying mink growth and development. Consequently, a total of 25,954 gene expression profiles were acquired throughout the growth and development stages of mink at 45, 90, and 120 days. Among these profiles, 2607 genes exhibited significant differential expression (|log2(fold change)| ≥ 2 and p_adj < 0.05). GO and KEGG enrichment analyses revealed that the differentially expressed genes were primarily associated with the mitotic cell cycle process, response to growth factors, muscle organ development, and insulin resistance. Furthermore, GSEA enrichment analysis demonstrated a significant enrichment of differentially expressed genes in the p53 signaling pathway at 45 days of age. Subsequent analysis revealed that genes associated with embryonic development (e.g., PEG10, IGF2, NRK), cell cycle regulation (e.g., CDK6, CDC6, CDC27, CCNA2), and the FGF family (e.g., FGF2, FGF6, FGFR2) were all found to be upregulated at 45 days of age in mink, which suggested a potential role for these genes in governing early growth and developmental processes. Conversely, genes associated with skeletal muscle development (PRVA, TNNI1, TNNI2, MYL3, MUSTN1), a negative regulator of the cell cycle gene (CDKN2C), and IGFBP6 were found to be up-regulated at 90 days of age, suggesting their potential involvement in the rapid growth of mink. In summary, our experimental data provide robust support for elucidating the regulatory mechanisms underlying the growth and development of mink. Full article

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods. Full article

Inosine monophosphate (IMP) is a substance that enhances flavor and plays a crucial role in the umami taste of chicken muscle. It is also an influential factor in determining chicken’s economic value. However, the molecular regulatory network underlying the IMP content in muscle remains unclear. To address this issue, we performed transcriptome sequencing on 20 pectoralis major muscle samples from 120-day-old Guangde feathered-leg chicken and used weighted gene co-expression network analysis (WGCNA) to identify key regulatory factors that influence IMP content. The weighted gene co-expression network was constructed using a total of 16,344 genes, leading to the identification of 20 co-expression gene modules. Among the modules that were identified, it was observed that the purple module (R = −0.51, p = 0.02) showed a significant negative correlation with the IMP content. This suggests that the genes within the purple module had the ability to regulate the IMP content. A total of 68 hub genes were identified in the purple module through gene significance (GS) > 0.2 and module membership (MM) > 0.8. The STRING database was used for a protein–protein interaction (PPI) network of hub genes. Furthermore, troponin I type 1 (TNNI1), myozenin 2 (MYOZ2), myosin light chain 2 regulatory cardiac slow (MYL2), and myosin light chain 3 regulatory cardiac slow (MYL3) involved in the “ATP-dependent activity”, “cAMP signaling pathway” and “cGMP-PKG signaling pathway” were identified as central regulators that contribute to IMP content. These results offer valuable information into the gene expression and regulation that affects IMP content in muscle. Full article

Wannanhua (WH) is a pig breed indigenous to Anhui Province, China. This breed has a high intramuscular fat (IMF) content, making it an ideal model for investigating lipid deposition mechanisms in pigs. IMF content is one of the main indicators of meat quality in pigs and is regulated by multiple genes and metabolic pathways. Building upon our prior transcriptomic investigation, the present study focused on the longissimus dorsi muscle tissue of Wannanhua (WH) pigs in the rapid fat-deposition stages (120 and 240 days of age). Employing 4D label-free quantitative proteomic analysis, we identified 106 differentially expressed proteins (DEPs). Parallel reaction monitoring (PRM) technology was used to verify the DEPs, and the results showed that the 4D label-free results were reliable and valid. Functional enrichment and protein–protein interaction analyses showed that the DEPs were mainly involved in the skeletal-muscle-associated structural proteins, mitochondria, energy metabolism, and fatty acid metabolism. By integrating transcriptomic data, we identified seven candidate genes including ACADL, ACADM, ANKRD2, MYOZ2, TNNI1, UCHL1, and ART3 that play a regulatory role in fat deposition and muscle development. These findings establish a theoretical foundation for future analyses of lipid deposition traits, contributing to potential enhancements in pig meat quality during breeding and advancing the selection process for Chinese indigenous breeds. Full article

Intramuscular fat (IMF) content is a key determinant of pork quality. Controlling the genetic and physiological factors of IMF and the expression patterns of various genes is important for regulating the IMF content and improving meat quality in pig breeding. Growing evidence has suggested the role of genetic factors and breeds in IMF deposition; however, research on the sex factors of IMF deposition is still lacking. The present study aimed to identify potential sex-specific biomarkers strongly associated with IMF deposition in low- and high-IMF pig populations. The GSE144780 expression dataset of IMF deposition-related genes were obtained from the Gene Expression Omnibus. Initially, differentially expressed genes (DEGs) were detected in male and female low-IMF (162 DEGs, including 64 up- and 98 down-regulated genes) and high-IMF pigs (202 DEGs, including 147 up- and 55 down-regulated genes). Moreover, hub genes were screened via PPI network construction. Furthermore, hub genes were screened for potential sex-specific biomarkers using the least absolute shrinkage and selection operator machine learning algorithm, and sex-specific biomarkers in low-IMF (troponin I (TNNI1), myosin light chain 9(MYL9), and serpin family C member 1(SERPINC1)) and high-IMF pigs (CD4 molecule (CD4), CD2 molecule (CD2), and amine oxidase copper-containing 2(AOC2)) were identified, and then verified by quantitative real-time PCR (qRT-PCR) in semimembranosus muscles. Additionally, the gene set enrichment analysis and single-sample gene set enrichment analysis of hallmark gene sets were collectively performed on the identified biomarkers. Finally, the transcription factor-biomarker and lncRNA-miRNA-mRNA (biomarker) networks were predicted. The identified potential sex-specific biomarkers may provide new insights into the molecular mechanisms of IMF deposition and the beneficial foundation for improving meat quality in pig breeding. Full article