Search Results (116)

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

Late-onset Fuchs endothelial corneal dystrophy (FECD) is a hereditary, progressive, bilateral and irreversible disorder that is characterized by thickening of Descemet’s membrane, microscopic collagenous protuberances known as guttae, and accelerated loss of corneal endothelial cells. Patients initially complain of blurred vision, and as the disease progresses, painful epithelial edema develops. Untreated cases of FECD often result in blindness, and then, the only treatment is corneal transplantation. DNA polymorphisms in many genes have been implicated, among them TCF4 on chromosome 18q, encoding a transcription factor protein E2-2, which is involved in regulating cellular growth and differentiation in the cornea. In our previous published study, we confirmed the association of an intronic TCF4 SNP (rs613872) with the disease in our population. The purpose of this present study is to further investigate another intronic point of interest in the same gene, the CTG18.1 trinucleotide repeat expansion. DNA was isolated from EDTA blood from a well-ascertained group of 36 Greek patients with FECD (Krachmer scale ≥ 2) and 58 healthy individuals, age- and sex-matched after obtaining their informed consent. STR-PCR and triplet-repeat primed PCR (TP-PCR) were performed, followed by gel electrophoresis and fragment analysis on an ABI SeqStudio genetic analyzer. Our real-time qPCR genotyping method was used for the SNP in the LightCycler (Roche). Statistical analysis of both genetic results was performed with SPSS and SNPStats. Full article

The pathogenesis of rheumatoid arthritis involves a complex interplay of genetic predisposition, environmental factors, and autoimmune mechanisms that lead to chronic inflammation of the synovial membrane. Fc-like receptor 3 (FcRL3) is a receptor encoded by the FCRL3 gene, located on the long arm of chromosome 1 at 1q23.1. Polymorphisms in the promoter region of FCRL3, rather than elsewhere in the gene, primarily affect the level of protein expression, which is of clinical significance. Understanding the structure of FcRL3, particularly in the context of genetic variants, is therefore important for elucidating the pathogenesis of autoimmune diseases. Detailed knowledge of the molecular architecture of immune receptors such as FcRL3 is also essential for advancing our understanding of immune function and for guiding the development of targeted therapeutic strategies in autoimmune disease. In this article, we discuss the role of FcRL3 in the pathophysiology and potential therapy of rheumatoid arthritis. Full article

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The pathophysiology of IBD is multifactorial including genetic predisposition, mucosal and epithelial dysfunction, environmental injury, and both innate and adaptive immune response abnormalities. Several predisposing genetic factors have been associated with IBD explaining the strong hereditary risk for both CD and UC. For example, Caspase Recruitment Domain 9 (CARD9) variant rs10781499 increases risk for IBD, while other variants are specific to either CD or UC. CD is related to loss-of-function mutations in the nucleotide oligomerization domain containing the protein 2 (NOD2) gene and Autophagy-Related 16-like 1 (ATG16L1) gene. UC risk is increased particularly in Chinese populations by the A-1661G polymorphism of the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene. This abnormal CTLA-4 interferes with B- and T-cell responses causing predisposition to autoimmune conditions. Previous studies suggested that IBD results from breakdown of the adaptive immune system, primarily of T-cells. However, new evidence suggests that a primary breakdown of the innate immune system in both CD and UC increases susceptibility to invasion by viruses and bacteria, with a compensatory overactivation of the adaptive immune system as a result. When this viral and microbial invasion continues, further damage is incurred, resulting in a downward cycle of further cytokine activation and epithelial damage. Released biomarkers also affect the permeability of the epithelial membrane, including lactoferrin, nitric oxide (NO), myeloperoxidase (MPO) and its activation of hypochlorous acid, matrix metalloproteinases (MMPs), especially MMP-9, omentin-1, and others. Increased macrophage and dendritic cell dysfunction, increased neutrophil activity, increased numbers of innate lymphoid cells, increased T-cells with decreased regulatory T-cells (Tregs), and changes in B-cell populations and immunoglobulin (Ig) functions are all associated with IBD. Finally, treatment of IBD has typically consisted of medical management (e.g., aminosalicylates and corticosteroids) and lifestyle modification, and surgical intervention in extreme cases. New classes of medications with more favorable side effect profiles include anti-integrin antibodies, vedolizumab, etrolizumab, and carotegrast methyl. Additionally, fecal microbiota transplant (FMT) is a newer area of research for treatment of IBD along with TNF-blockers, JAK inhibitors, and S1PR modulators. However, expense and long preparation time have limited the usefulness of FMT. Full article

Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation—classical, lectin, and alternative—are implicated in developing cardiac damage, inflammation, and hypertrophy due to infectious and non-infectious causes, autoimmune diseases, genetic polymorphisms, and forms of complement dysregulation. Of interest in this review is the role of the complement system, a collection of soluble and membrane-bound proteins that mediate inflammatory processes through interactions with signaling molecules and immune cells. This review comprehensively discusses the roles of these complement pathways in contagious, chronic inflammatory, genetic, and metabolic diseases. An overview of the completed and terminated clinical trials aimed at preventing cardiovascular mortality by targeting various aspects of the complement system and inflammatory reaction is included. Most current treatments for cardiac inflammation and remodeling primarily target the renin–angiotensin–aldosterone system (RAAS), which prevents further remodeling by reducing myocardial workload. However, moving forward, there may be a place for emerging anti-complement therapeutics, which impair the inflammatory response that generates hypertrophy itself. Full article

Eggshell membrane (ESM) is composed of approximately 90% protein. Our previous studies in healthy adults demonstrated that two months of daily ESM intake improved respiratory function, zigzag walking speed, and skin elasticity. The present study aims to address the knowledge gap regarding the in vivo effects of ESM in the context of inflammatory bowel disease (IBD). Proteomic analysis was performed on powdered ESM used as a dietary supplement. To investigate its pharmacokinetics in mice, tritium (³H)-labeled ESM was prepared using the ⁶Li(n,α)³H nuclear reaction. The therapeutic potential of ESM was further examined in a 2.0% dextran sulfate sodium (DSS)-induced murine model of IBD. In addition, fecal samples from both mice and healthy human subjects were analyzed using a modified terminal restriction fragment length polymorphism (T-RFLP) method. Lysozyme C (LYZ) was the most abundant protein (47%), followed by lysyl oxidase (12%) in ESM used in this study. ³H-ESM was mixed with MediGel, and orally administered to mice. Radioactivity levels were measured in blood, organs (duodenum, small intestine, large intestine, liver, kidney, lung, skin), and rectal feces at 0.5, 2, 5, 24, 48, and 72 h post-administration. Radioactivity in feces indicated excretion of undigested components, while systemic distribution suggested potential whole-body effects of ESM. Oral ESM and LYZ significantly alleviated body weight loss, diarrhea, and hematochezia in a DSS-induced murine model of IBD, leading to a significantly lower disease activity index on day 3 and showing a similar trend on day 5. Gut microbiota analysis showed increased Bacteroidales in the DSS group, while the ESM + DSS group maintained levels similar to the control. In humans, a double-blind, randomized controlled trial was conducted to evaluate the effects of ESM on gut microbiota in healthy adults. Participants received either ESM or placebo for 8 weeks. revealed a significant increase in alpha diversity at weeks 1 and 8 in the ESM group (p < 0.05), with between-group differences evident from week 1 (p < 0.01). ESM intake reduced Bacteroides and significantly increased Bifidobacterium and Lactobacillales at weeks 4 and 8. These findings suggest ESM supplementation promotes beneficial modulation of gut microbiota. These findings suggest that ESM, through its major protein components such as LYZ, may serve as a promising dietary intervention for maintaining intestinal health and mitigating inflammation in the context of IBD. Full article

Seed oil and protein contents are critical agronomic traits that determine soybean quality. However, the key loci and corresponding genes controlling these quality traits remain to be elucidated. Here, we performed bulked segregant analysis by sequencing (BSA-seq) using an F4 population derived from a cross between the cultivars Heinong 35 (HN35) and Dengke 3 (DK3). A major soybean oil and protein quantitative trait locus (QTL) designated as q-OP18 was identified on chromosome 18, and the sugar transporter gene GmSWEET46 was further cloned. Haplotype analysis revealed that a single-nucleotide polymorphism (SNP) in the sixth exon of GmSWEET46 results in an amino acid change between HN35 and DK3 and is associated with seed oil and protein content, suggesting its important role in determining seed quality in soybean. GmSWEET46 is expressed during the early stages of seed and pod development and localizes to the plasma membrane, indicating its potential function as a sugar transporter. Further studies demonstrated that GmSWEET46 can regulate seed protein content, oil content, and seed size in Arabidopsis and soybean. Collectively, this study provides a novel locus and gene for regulating soybean seed traits and offers valuable resources for the breeding of high-quality and high-yielding soybean cultivars. Full article

Hearing loss is often caused by genetic and environmental factors, with inherited mutations responsible for 50–60% of cases. The GJB2 gene, encoding connexin 26, is a major contributor to nonsyndromic sensorineural hearing loss (NSHL) due to its role in cellular communication critical for auditory function. In Taiwan, common deafness-associated genes include GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. The most common pathogenic genes is GJB2 mutations and the hearing level in children with GJB2 p.V37I/p.V37I or p.V37I/c.235delC was estimated to deteriorate at approximately 1 decibel hearing level (dB HL)/year. We found another common mutation in Taiwan Biobank, GJB2 p.I203T, which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest GJB2 whole genetic screening is recommended for clinical management and prevention strategies in Taiwan. This study used data from the Taiwan Biobank to analyze allele frequencies of GJB2 gene variants. Predictive software (PolyPhen-2 version 2.2, SIFT for missense variants 6.2.1, MutationTaster Ensembl 112 and Alphamissense CC BY-NC-SA 4.0) assessed the pathogenicity of specific mutations. Additionally, 82 unrelated NSHL patients were screened for mutations in these genes using PCR and DNA sequencing. The study explored the correlation between genetic mutations and the severity of hearing loss in patients. Several common GJB2 mutation sites were identified from the Taiwan Biobank, including GJB2 p.V37I (7.7%), GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%). Bioinformatics analysis classified GJB2 p.I203T as pathogenic, while GJB2 p.V27I and GJB2 p.E114G were considered polymorphisms. Patients with GJB2 p.I203T mutation experienced more severe hearing loss, emphasizing the potential interaction between the gene in auditory impairment. The mutation patterns of GJB2 in the Taiwanese population are similar to other East Asian regions. Although GJB2 mutations represent the predominant genetic cause of hereditary hearing loss, the corresponding mutant proteins exhibit detectable aggregation, particularly at cell–cell junctions, suggesting at least partial trafficking to the plasma membrane. Genetic screening for these mutations—especially GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%)—is essential for the effective diagnosis and management of non-syndromic hearing loss (NSHL) in Taiwan. We found GJB2 p.I203T which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest whole GJB2 gene sequencing in genetic screening is recommended for clinical management and prevention strategies in Taiwan. These findings have significant clinical and public health implications for the development of preventive and therapeutic strategies. Full article

Background and Objectives: Hypocitraturia is a major risk factor for calcium-containing kidney stone disease. Citrate inhibits stone formation by binding calcium in the urine. The SLC13A2 gene encodes the sodium-dependent dicarboxylate cotransporter 1 (NaDC1), a membrane transport protein that facilitates citrate reabsorption in the proximal renal tubules. Variants in this gene, such as rs11568476 (V477M), have been shown to significantly impair transporter activity. This study aimed to investigate the presence of the rs11568476 polymorphism in SLC13A2 and its association with hypocitraturia in Turkish patients with calcium-containing kidney stones. To our knowledge, this is the first genetic study evaluating this polymorphism in a Turkish cohort. Materials and Methods: This prospective cross-sectional study included 90 patients diagnosed with calcium-containing kidney stones at Düzce University Faculty of Medicine, Department of Urology. Based on 24 h urinary citrate levels, patients were divided into two groups: normocitraturic (n = 38) and hypocitraturic (n = 52). Blood and 24 h urine samples were analyzed for biochemical parameters. The rs11568476 polymorphism in SLC13A2 was analyzed using Real-Time PCR. Results: There were no significant differences between the two groups in terms of age, gender, and most biochemical parameters. Serum uric acid levels were significantly higher in the hypocitraturic group (p = 0.002), whereas family history of stone disease was more prevalent in the normocitraturic group (p = 0.024). Genetic analysis revealed no polymorphism in the rs11568476 region; all patients exhibited the homozygous wild-type genotype (GG). Conclusions: No association was observed between the rs11568476 polymorphism and hypocitraturia in this cohort. The absence of the polymorphism suggests that this variant may be rare or absent in the Turkish population. These findings highlight the importance of investigating additional genetic and environmental contributors to hypocitraturia and nephrolithiasis through larger, multicenter studies. Full article

Soybean mosaic virus (SMV) is a major viral pathogen that causes significant yield losses and a reduction in seed quality in susceptible soybean cultivars. Resistance breeding is the most effective, economical, and eco-friendly strategy for prevention of SMV-induced damage. Accurate and convenient assessment of SMV resistance is an essential prerequisite for resistance breeding. In this study, we constructed a green fluorescent protein (GFP)-tagged SMV recombinant virus (SMV-GFP) by yeast homologous recombination technology. It was proved that the recombinant virus can not only be used to track the viral infection process in Nicotiana benthamiana and soybean, but also to quantify the viral load based on relative fluorescence area (RFA) value. Using this recombinant virus, the resistance of 286 soybean germplasms from Northeast China to SMV was evaluated. A genome-wide association study (GWAS) was conducted using the RFA values of the 286 soybean accessions to find possible SMV-resistance genes. The results revealed 72 single nucleotide polymorphism (SNP) loci on chromosome 13 closely associated with SMV resistance, and a total of 40 genes were discovered within the candidate regions. By integrating the results of gene functional annotation and haplotype analysis, Glyma.13g176600 encoding a membrane attack complex/perforin (MACPF) domain-containing protein and Glyma.13g177000 encoding a DUF761-containing protein were identified as the most probable candidate genes associated with SMV resistance. Overall, the GFP-based rapid evaluation system developed in this study will facilitate breeding for resistance to SMV in soybean. Full article

Cytochrome P450 (CYP450) enzymes play an essential role in the metabolism of drugs, particularly in phase I metabolic reactions. In this article, we present a comprehensive review of fifteen selected enzymes belonging to the CYP450 family. The enzymes included in this analysis are CYP7A1, CYP3A4, CYP3A5, CYP2D6, CYP2E1, CYP2C8, CYP2C18, CYP2C9, CYP2C19, CYP2B6, CYP2A6, CYP2A13, CYP1B1, CYP1A1, and CYP1A2. We examined the influence of natural, polymorphic variations within their primary amino acid sequences on their enzymatic function and mechanisms of action. To begin, we compiled a dataset of naturally occurring polymorphic variants for these enzymes. This was achieved through a detailed analysis of entries in the UniProt database, as well as an extensive review of the current scientific literature. For each variant, we included commentary regarding its potential impact on enzyme activity or drug response, based on evidence observed in in vitro experiments, in vivo studies, or clinical trials. Particular emphasis was placed on how such polymorphisms might alter the metabolism of xenobiotics, thereby potentially affecting pharmacological outcomes. In this respect, the work represents the first comprehensive source in the scientific literature that systematically gathers and organizes data on CYP450 polymorphisms, including an assessment of their potential significance in processes mediated by these enzymes. A more detailed comparison of the polymorphism-related in vitro studies is devoted to CYP3A4, an enzyme that displays the largest fraction of clinically significant polymorphs. Secondly, we aimed to establish possible molecular explanations for why specific polymorphisms exhibit clinically or experimentally observable effects. To explore this, we performed a qualitative structural analysis of the enzymes, focusing on shared structural characteristics among the examined members of the CYP450 family. The results of this analysis demonstrate that there is no single universal mechanism by which polymorphisms influence the function of CYP450 enzymes. Instead, the mechanisms vary and may include alterations in the orientation of the enzyme within the lipid membrane, changes affecting the association or dissociation of substrates and products at the active site, structural stabilization or destabilization of the enzyme’s reactive centers, modifications in the way the enzyme interacts with its ligand, or alterations in the character of the interface involved in contact with its redox partner (electron transfer protein). Furthermore, among the polymorphisms that significantly impact enzyme function, mutations involving the substitution of arginine residues for other amino acids appear to be overrepresented. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms. Full article

Phosphorus (P) is an essential nutrient for plant growth, and low-phosphorus (LP) stress significantly limits cotton productivity. Here, we conducted single- and multi-locus genome-wide association studies (GWASs) on four LP-related traits using 419 upland cotton (Gossypium hirsutum L.) accessions genotyped with 2.97 million single-nucleotide polymorphisms (SNPs). Phenotypic analysis reveals substantial variation under LP stress, with LP-SDW showing the highest coefficient of variation (33.69%). The GWASs identified thousands of significant SNPs, including pleiotropic loci associated with multiple traits. Chromosomes A08, D09, and D12 harbored novel associated signals. Multi-locus models significantly enhanced detection sensitivity, identifying 123 SNPs undetected by single-locus approaches. Functional annotations prioritized six candidate genes near associated SNPs, including GhM_A08G1315 (remorin protein) and GhM_D06G1152 (carotenoid cleavage dioxygenase), whose LP-induced expression patterns were validated by qRT-PCR. These genes are implicated in membrane signaling, root architecture modulation, and hormone metabolism. Our findings provide novel genetic insights into LP tolerance and establish a foundation for breeding phosphorus-efficient varieties through marker-assisted selection in cotton. Full article

α-Synuclein (αS) interacts with lipid membranes in neurons to form amyloid fibrils that contribute to Parkinson’s disease, and its non-amyloid-β component domain is critical in the fibrillation. In this study, the salt (NaCl) effect on the membrane interaction and fibril formation of αS_57–102 peptide (containing the non-amyloid-β component domain) was characterized at the molecular level because the αS_57–102 fibrils exhibited structural polymorphism with two morphologies (thin and thick) in the presence of NaCl but showed one morphology (thin) in the absence of NaCl. The membrane-bound conformation (before fibrillation) of αS_57–102 had two helical regions (first and second) on the membrane regardless of salt, but the length of the first region largely shortened when NaCl was present, exposing its hydrophobic area to the solvent. The exposed region induced two distinct pathways of fibril nucleation, depending on the molar ratios of free and membrane-bound αS_57–102: one from the association of free αS_57–102 with membrane-bound αS_57–102 and the other from the assembly among membrane-bound αS_57–102. The differences mainly affected the β-strand orientation and helical content within the fibril conformations, probably contributing to the thickness degree, leading to structural polymorphism. Full article

Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder characterized by recurrent fevers and inflammation of the serous membranes in the abdomen, lungs, and joints. Currently, the standard treatment of FMF includes colchicine, which is an alkaloid, derived from Colchicum autumnale. Colchicine’s efficacy in FMF is well-established as it is used both to prevent acute attacks and reduce the risk of long-term complications. However, despite these available treatments, 5–10% of patients exhibit resistance to the drug. It has been demonstrated that polymorphisms in several genes involved in inflammation can influence treatment outcomes and the risk of FMF complications like amyloidosis. Among them, some research focused on polymorphism affecting adenosine triphosphate (ATP)-binding cassette sub-family B member 1 (ABCB1) gene encoding for P-glycoprotein. P-glycoprotein is considered a key transporter protein as it regulates the absorption, distribution, and excretion of several drugs, including colchicine. In diseases like FMF, ABCB1 polymorphisms have been shown to affect the response to colchicine, potentially leading to treatment resistance or altered toxicity. Based on this evidence, this systematic review aims to analyze available evidence on ABCB1-mediated colchicine transport and its clinical implications in FMF, showing how relevant ABCB1 variants are in response to therapy. Full article