Search Results (163)

Colorectal cancer (CRC) remains a leading cause of cancer mortality, yet no systematic effort has linked druggable CRC driver genes to downstream ion channel effectors. We integrated differential expression analysis, weighted gene co-expression network analysis (WGCNA), and protein–protein interaction (PPI) network pharmacology to identify CRC hub genes and their ion channel connections, validated by dual single-cell perturbation approaches: variational graph autoencoder-based virtual knockout (VGAE-KO) and experimental HCT116 CRISPRi Perturb-seq (6 genes, 8445 cells). WGCNA identified 100 hub genes spanning three functional programs. Ribosomal proteins link to K⁺ channels (RPS21 → KCNQ2, targetable by EMA-approved ataluren, passed dual validation at 97.8th–98.7th percentile). RNA processing genes connect to Cl⁻ channels (LSM7 → CLIC1, strongest signal at 99.8th–99.4th percentile). Immune checkpoint receptors (LAG3, CD27) connect via PPI intermediates to ${\mathrm{Ca}}^{2+}$ and K⁺ channels, targetable by relatlimab (FDA-approved) and varlilumab (Phase 2). This work maps previously unknown links between CRC driver genes and ion channel regulation, with the ataluren-RPS21-KCNQ2 axis ready for pharmacological testing. Full article

Introduction: Epilepsy syndromes show marked clinical and genetic heterogeneity, with numerous functionally diverse genes involved in their etiology. Next-generation sequencing (NGS) has facilitated the identification of many monogenic epilepsy syndromes and enables earlier, more accurate diagnosis in pediatric patients. Materials and Methods: This study analyzes the molecular profiles of 87 pediatric patients with various forms of epilepsy in whom pathogenic or likely pathogenic variants were identified. Next-generation sequencing (NGS) using multi-gene epilepsy panels or whole-exome sequencing (WES) was performed. Results: A total of 88 pathogenic or likely pathogenic variants were detected in 48 epilepsy-related genes; 30 variants occurred de novo. SCN1A and KCNQ2 were the most frequent contributors (12.6% and 9.2%, respectively). The highest percentage of positive diagnoses (48%) was observed in patients with developmental and epileptic encephalopathy (DEE), with variants identified in genes including ALG13, ATP1A2, CACNA1A, CDKL5, CHD2, GABRG2, ITPA, KCNQ2, PCDH19, SCN1A, SCN2A, SCN3A, SCN8A, SMC1A, SPTAN1, STXBP1, and UBA5. Pathogenic variants in ANKRD11 were found in four patients with KBG syndrome, while other genes appeared sporadically. Conclusions: Targeted massively parallel sequencing is an effective diagnostic tool for pediatric epilepsy. The presence of numerous single-case findings highlights the high genetic heterogeneity of epilepsy. This approach enabled more precise diagnoses that would not have been achieved through clinical evaluation alone, underscoring the importance of genetic testing for prognosis and treatment planning in pediatric patients with unexplained epilepsy. Full article

Background/Objectives: Cardiac arrhythmias are among the leading causes of sudden cardiac death (SCD). Pathogenic variants in potassium channel genes play a key role in inherited arrhythmia syndromes, yet their contribution in Central Asian populations remains poorly characterized. Methods: We performed targeted next-generation sequencing (NGS) using a 96-gene custom Haloplex panel in 79 Kazakhstani patients with clinically diagnosed arrhythmias, including atrioventricular block, sick sinus syndrome, and atrial fibrillation. Detected variants in potassium channel genes were classified according to ACMG guidelines and correlated with clinical phenotypes. Results: A total of 52 variants were identified across 11 potassium channel genes. Two likely pathogenic variants (KCNH2 p.Cys66Gly and p.Arg176Trp) and six variants of uncertain significance (VUS) in KCNQ1, KCNE2, KCNE3, and KCNJ8 were detected. Two novel previously unreported variants were found in KCNE5 and KCND3. Patients harboring pathogenic variants commonly presented with early-onset arrhythmias or a positive family history of cardiovascular disease. Carriers of KCNH2 variants exhibited mild QT prolongation and recurrent syncope. Conclusions: This is the first genetic study of potassium channel gene mutations in Kazakhstani patients with cardiac arrhythmias. The detection of pathogenic and novel variants highlights the clinical utility of integrating genetic testing into diagnostic and management pathways for arrhythmia syndromes. Population-specific genomic data are essential for improving risk stratification, guiding medication safety, and enabling cascade family screening in Central Asia. Full article

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

This study evaluated the clinical utility of a polygenic risk score (PRS)-based multigene panel test for predicting diabetes mellitus (DM) in a healthy population. A total of 302 individuals underwent genetic testing using the HelloGene™ DM panel, which includes four DM-related single nucleotide polymorphisms (CDKAL1, HHEX, KCNQ1, and TCF7L2). PRS values were calculated using an algorithm developed from the Korean Genome and Epidemiology Study (KoGES; n = 39,605), and participants were classified into four genetic risk groups (low, moderate, high, and very high). Fasting blood glucose, glycated hemoglobin (HbA1c), and body mass index were assessed at baseline and after at least three years of follow-up, and lifestyle factors including smoking, alcohol consumption, and exercise status were recorded. No significant differences in age, sex, or lifestyle habits were observed among PRS groups. The very high-risk group showed significantly higher follow-up fasting blood glucose levels (p = 0.001) and higher baseline and follow-up HbA1c levels (p = 0.0025 and p = 0.001, respectively), as well as a 4.5-fold increased risk of developing DM compared with other groups. Smoking significantly modified genetic risk, with smokers in the very high-risk group showing a 25% higher likelihood of developing DM. CDKAL1 and TCF7L2 variants were most prevalent in the moderate- and high-risk groups, while HHEX variants in the high-risk group showed the greatest susceptibility, particularly among current smokers. Overall, PRS-based genetic testing demonstrated potential clinical utility for stratifying individuals according to relative diabetes risk, highlighting a possible interaction between genetic susceptibility and lifestyle factors such as smoking Full article

Synthetic cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) are potent psychostimulants with high abuse potential, yet their systemic toxicity and neurobehavioral effects remain poorly characterized during early development. Using Danio rerio (zebrafish) embryos and larvae, we performed an integrated assessment of the cardiotoxic, behavioral, and molecular effects of MDPV. Acute exposure of 3 days post-fertilization (dpf) embryos produced a marked, concentration-dependent bradycardia and atrioventricular (AV) conduction block, leading to reduced ventricular activity and complete AV dissociation at the highest concentrations (EC₅₀ = 228 µM). Quantitative analysis of ventricular motion revealed a significant decrease in cardiac output (CO) at all tested concentrations and a reduction in ejection fraction (EF) only at 480 µM, while fractional shortening (FS) and stroke volume (SV) remained unchanged, indicating predominant chronotropic and conduction effects with secondary contractile impairment. In 5 dpf larvae, MDPV caused a sustained, concentration-dependent decrease in basal locomotor activity (EC₅₀ = 2.51 µM) but did not affect prepulse inhibition (PPI) of the acoustic startle response (ASR), unlike dextroamphetamine, which enhanced PPI via dopaminergic D₂ receptor activation. Short-term (2 h) exposure of 3 dpf embryos to 0.4–400 µM MDPV induced transcriptional changes in dopaminergic and stress-responsive genes, whereas expression of major repolarizing potassium channel genes (kcnh6a and kcnq1) remained unaltered. Collectively, these results demonstrate that MDPV exerts potent negative chronotropic effects likely through direct functional interference with cardiac repolarization, while neurobehavioral effects occur at concentrations nearly two orders of magnitude lower than cardiotoxic thresholds, supporting zebrafish as a predictive model for the integrative assessment of psychostimulant toxicity. Full article

Background and Objectives: Infantile spasms (ISs), or West syndrome (WS), represent an early-onset epileptic encephalopathy in which diverse structural, genetic, metabolic, infectious, and neurocutaneous conditions converge on a shared pattern of hypsarrhythmia, clustered spasms, and later developmental impairment. Growing use of genomic diagnostics has revealed that variants in STXBP1, KCNQ2, GRIN2A, GRIN2B, and TSC-related genes are more common than previously recognized and can be linked to partially actionable pathways. This review aimed to synthesize current evidence on the multifactorial etiology, network-based pathogenesis, and evolving targeted therapies for ISs, with particular attention to TSC-related forms. Materials and Methods: A structured narrative review was undertaken of publications from 1990 to 2025 in PubMed, Scopus, Web of Science, and Embase using terms related to ISs, WS, genetics, mTOR, ACTH, vigabatrin, ketogenic diet, and precision therapies. Authoritative guidance from ILAE and AAN was incorporated. Clinical, molecular, and therapeutic data were grouped under etiological, pathogenetic, and management domains. Results: Structural causes remained the largest group, but combined genetic, genetic–structural, and metabolic etiologies accounted for about one third of contemporary cohorts. Early network disruption involving cortex, thalamus, basal ganglia, and brainstem, together with imbalances in NGF, BDNF, and IGF-1, explained why distinct primary insults produce a uniform electroclinical phenotype. Early treatment with ACTH or high dose prednisolone, with or without vigabatrin, was consistently associated with higher electroclinical remission and better developmental outcome. Everolimus and related mTOR inhibitors showed benefit in TSC-associated ISs, while agents directed at NMDA receptors or KCNQ channels are emerging for genotype defined subgroups. Conclusions: ISs should be approached as a heterogeneous but mechanistically convergent disorder in which rapid diagnosis, parallel genetic testing, and early disease modifying therapy improve prognosis. Integration of molecular profiling with standardized outcome monitoring is likely to move management from symptomatic seizure control to pathway-specific intervention. Full article

The ketogenic diet (KD) is a metabolic intervention characterized by high fat and very low carbohydrate intake, showing significant metabolic, neuroprotective, and therapeutic effects. However, its efficacy varies widely due to individual genetic and epigenetic factors. This review synthesizes current knowledge of genes most strongly associated with KD response, including polymorphisms in FTO, APOA2, PPAR, SCN1A, KCNQ2, STXBP1, CDKL5, the MODY gene group, and SLC2A1, which shape outcomes across lipid metabolism, energy expenditure, inflammation, and neurotransmission. Epigenomic modifications induced by a KD, such as changes in DNA methylation and histone acetylation involving BDNF, SLC12A5, KLF14, and others, modulate functional metabolic and neurological effects. Sex and age further modulate KD effects through distinct patterns of gene activation and hormonal interactions. These variables together impact metabolic and neurological outcomes and are critical for developing personalized nutrition and disease management strategies. Based on the reviewed evidence, genetic and epigenetic profiling can help identify patients who are likely to benefit from a KD (e.g., GLUT1DS, PDH deficiency) and those in whom a KD may be ineffective or harmful (e.g., SCOT or SLC2A1-independent defects). The review concludes that genetic and epigenetic profiling is recommended for personalized dietary interventions. Full article

Objectives: One of the major trends in modern computational toxicology is the development of explainable predictive tools. However, the complex nature of the mechanistic representation of biological organisms and the lack of relevant data remain limiting factors. Methods: This work provides a publicly available dataset of 12,654 compounds with mouse intravenous ${\mathrm{LD}}_{50}$ values, as well as docking scores (Vina-GPU 2.0) against 44 toxicity-associated proteins. NIH and Brenk filters were applied to refine the chemical space. Results: Across the entire protein panel, the human ether-a-go-go–related gene channel (hERG/KCNH2), vasopressin receptor 1A (AVPR1A), the L-type voltage-gated calcium channel Cav1.2 (CACNA1C), the potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) and endothelin receptor A (EDNRA) showed the strongest association with acute toxicity. Statistically significant differences were found in the distribution of ${\mathrm{LD}}_{50}$ values for compounds that bind antitargets compared with non-binders. Using known bioactive molecules such as anisodamine, butaperazine, soman, and several cannabinoids as examples confirmed the effectiveness of inverse docking for elucidating mechanism of action. Conclusions: The dataset offers a resource to advance transparent, mechanism-aware toxicity modeling. The data is openly available. Full article

Buffalo milk plays a vital role in the dairy industry, with milk yield regulated by both transcriptomic and epigenetic mechanisms. While previous studies have primarily focused on differences among individuals or breeds, the epigenetic basis underlying milk yield variation in genetically identical animals remains poorly understood. In this study, we employed a cloned buffalo model and integrated whole-genome bisulfite sequencing (WGBS) with RNA sequencing (RNA-seq) to investigate how DNA methylation and transcriptional regulation contribute to milk yield variation. Results tentatively revealed that low-yielding buffalo exhibited globally reduced DNA methylation in mammary tissues, with distinct distribution patterns across genomic features and regulatory regions. Differentially methylated genes were enriched in PI3K-Akt, HIF-1, and immune-related pathways, whereas hypomethylated genes were associated with calcium signaling, cAMP pathways, and metabolic processes. Transcriptome analysis showed that high-yielding buffalo upregulated genes involved in lipid metabolism and cell proliferation, while low-yielding buffalo displayed enrichment in immune stress and amino acid metabolism. Integrative analysis identified 126 hypo-upregulated genes and highlighted hub regulators such as KLF6, NR4A1, ESR1, KCNQ1. Collectively, this study outlines a preliminary multi-omics regulatory landscape of milk yield variation in cloned buffalo, suggests the interplay between DNA methylation and transcription, provides preliminary insights into the potential interplay between DNA methylation and transcription, and suggests potential connections that merit further investigation. Full article

Calmodulin (CaM) plays a central role in cardiac excitation–contraction coupling by regulating ion channels, including the L-type calcium (Ca²⁺) channel Ca_v1.2 and the voltage-gated potassium (K⁺) channel K_v7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca²⁺ binding at the C-terminal lobe of CaM, altering its Ca²⁺-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca²⁺-dependent inactivation (CDI) of Ca_v1.2, prolonging Ca²⁺ influx, while also reducing activation of K_v7.1, thereby limiting repolarising K⁺ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca²⁺ and K⁺ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability. Full article

Background: Recurrent cervical cancer is one of the most defining threats to patient longevity, underscoring the need for prognostic models to identify high-risk patients. Objectives: The aim of the study is to integrate clinical data with the GSE44001 Dataset to identify key risk factors associated with the recurrence of cervical cancer. Patients are stratified into high-, moderate-, and low-risk groups using selected clinical and molecular features. Identifying a long non-coding RNA (lncRNA) gene signature associated with recurrent cervical cancer. Methods: From the total data collected, 138 recurrent cervical cancer patients were identified. GSE44001 Dataset is downloaded from the NCBI GEO Database. When using the GENCODE Annotation tool, the long non-coding RNA is filtered. The dataset is then linked with filtered long non-coding RNA. The Least Absolute Shrinkage Selection Operator (LASSO) is employed to find attributes in gene expression analysis. Risk factors of recurrent cervical cancer are identified. Risk value is assigned to each individual based on the selected lncRNAs and the corresponding overfitting coefficients. Result: The RNN Long Short-Term Memory model demonstrates a prognostic value, where high-risk patients experience a shorter duration of recurrence-free survival (p < 0.05). Individuals with a recurrence of cervical carcinoma, a progressive disease, were associated with the ATXN8OS marker, the C5orf60 indicator, and the INE1 index gene. In contrast, patients diagnosed at earlier stages are aligned with the KCNQ1DN marker, LOH12CR2 gauge, RFPL1S value, and KCNQ1OT1 indicator. Patients in moderate stages were primarily associated with the EMX2OS score. Conclusions: The research findings demonstrate that the nine-lncRNA signature, when combined with deep learning, offers a powerful approach for recurrence risk stratification in cervical cancer. Full article

Background: Stomach adenocarcinoma is a major contributor to worldwide mortality and significantly impacts life expectancy. The main objective of the current study was to identify a prognostic biomarker for stomach adenocarcinoma to advance translational medicine and improve patient outcomes. Method: various databases (GEPIA, UALCAN, miRNet, StarBase, and Kaplan Meier plotter) bioinformatics tools (cytoscape) and were used in this study. Results: Ten novel unfavorable prognosis-associated genes were identified. In addition, 41 potential miRNAs were predicted. ELAVL3-hsa-mir-29a-3p and CALCR-hsa-mir-29a-3p were identified as the two critical networks in the oncogenesis of stomach adenocarcinoma via bioinformatics analysis. Subsequently, the binding of lncRNAs to hsa-mir-29a-3p was predicted utilizing the starBase and miRNet databases. Following the execution of both expression and survival analyses for the predicted lncRNAs, it was determined that only one lncRNA, KCNQ1OT1, exhibited significant overexpression in stomach adenocarcinoma, and its elevated expression was associated with an unfavorable prognosis. Subsequently, we constructed a triple ceRNA network involving mRNA, miRNA, and lncRNA, which is associated with the prognosis of stomach adenocarcinoma. Conclusions: In summary, the current study provides an extensive ceRNA network that highlights novel prognostic biomarkers for stomach adenocarcinoma. Full article

Background: Developmental and Epileptic Encephalopathy (DEE) is a severe and heterogeneous neurological disorder in infancy/early childhood. DEE’s genetic and phenotypic variability complicates diagnosis and treatment. This retrospective study aimed to identify genetic variants and explore genotype–phenotype correlations in children with DEE using a targeted epilepsy gene panel (TGP) and Whole Exome Sequencing (WES). Patients and Methods: Medical records of children who underwent custom-designed 55-gene TGP and WES were reviewed. The diagnostic yield of each method was determined based on the detection of pathogenic (P) and likely pathogenic (LP) variants. Results: A total of 129 patients (66 males, 63 females) underwent TGP, which identified P/LP variants in 29 cases (22.48%). Variants were detected in SCN1A, KCNQ2, STXBP1, CDKL5, PCDH19, PLCB1, WWOX, SCN2A, FGF12, HCN1, SCN8A, and SLC35A2. WES further identified several variants in children with West syndrome. A TSC1 variant was detected in a patient without cutaneous stigmata of tuberous sclerosis complex. The NALCN variant in a patient was linked to Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 1. A CTBP1 variant associated with extremely rare Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome was detected in another patient. A PIEZO2 variant—associated with Marden–Walker syndrome—was found in a child with Early Infantile Developmental and Epileptic Encephalopathy. Conclusions: These findings highlight the extensive genetic heterogeneity and phenotypic variability of DEE. WES demonstrates substantial value in identifying novel gene-disease associations and may be considered as a first-tier diagnostic tool in epilepsy and DEE. Full article

Background/Objectives: Potassium (K⁺) channels are essential transmembrane proteins that regulate ion flow, playing a critical role in regulating action potentials and neuronal transmission. Although K⁺ channel openers (agonists, K⁺ Ag) are widely used in treating neurological and psychiatric disorders, their precise mechanisms of action remain unclear. Our study explored how K⁺ channel openers might influence the expression of voltage-gated K⁺ channels (Kv) in rat brain. Methods: Briefly, eight rats per group received intraperitoneal injections of diazoxide (Dia), chlorzoxazone (Chl), or flupirtine (Flu). Two hours post-injection, the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), dorsal hippocampus (dHIP), and ventral hippocampus (vHIP) were collected for mRNA expression analysis of various Kv. Results: Dia administration altered expression of Kcna6 in the NAc, dSTR, and vHIP, and Kcnq2 in the PFC, dSTR, and dHIP. The mRNA levels of Kcna2 and Kcna3 changed in the NAc, dHIP, and vHIP, while Kcna6 expression increased in the PFC, dHIP, and vHIP of rats treated with Chl. Injection of Flu resulted in altered expression for Kcna1 in the NAc, dSTR, and dHIP; Kcna3 in the PFC, NAc, dHIP, and vHIP; Kcna6 in the dSTR, dHIP, and vHIP; and Kcnq2 and Kcnq3 in the PFC, dHIP, and vHIP. We also found dose-dependent changes. Conclusions: To our knowledge, this is the first study to identify the effects of potassium channel openers on gene expression within the mesocorticolimbic and nigrostriatal dopaminergic systems. These findings reveal a novel molecular mechanism underlying the action of these drugs in the brain. Importantly, our results have broader implications for translational neuroscience, particularly in the context of repurposing FDA-approved drugs, such as diazoxide and chlorzoxazone, for the treatment of neurological disorders. Full article