Genetics research最新文献

{"title":"Exploring Deleterious Nonsynonymous SNPs in the <i>ACADM</i> Gene: Insights Into Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) via In Silico Analysis.","authors":"Muhammad Waleed Iqbal, Muhammad Shahab, Fakhreldeen Dabiellil, Yousef A Bin Jardan, Mohammed Bourhia, Xinxiao Sun, Qipeng Yuan","doi":"10.1155/genr/6682668","DOIUrl":"10.1155/genr/6682668","url":null,"abstract":"<p><p>Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), a potentially lethal metabolic disorder, is often associated with single-nucleotide polymorphisms (SNPs) in the acyl-CoA dehydrogenase, medium-chain (<i>ACADM</i>) gene. The current research investigates the structural and functional implications of these genetic variants through diverse bioinformatics techniques. A range of in silico techniques were utilized to thoroughly evaluate the effect of nonsynonymous SNPs. Molecular docking and molecular dynamics simulation evaluation comprehensively validated the mutational impact on protein's stability. Gene interaction analysis demonstrated that <i>ACADM</i> is involved in several cellular pathways and co-expression networks. Two nsSNPs, rs121434282 and rs200724875, were found to have a significant impact on the composition and functionality of <i>ACADM</i>. This research lays the foundation for precision medicine advancements, specifically against metabolic disorders. Thorough validation of the proposed nsSNPs, supported by animal models, is crucial for understanding their role in MCADD.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 ","pages":"6682668"},"PeriodicalIF":1.9,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12948724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Diverse Roles of the Histone-Like Nucleoid Structuring (H-NS) Protein in <i>Vibrio parahaemolyticus</i>.","authors":"Hao Tang, Yiquan Zhang","doi":"10.1155/genr/6503207","DOIUrl":"10.1155/genr/6503207","url":null,"abstract":"<p><p>The histone-like nucleoid structuring (H-NS) protein is a global transcriptional regulator critical for bacterial genome organization and gene expression. In <i>Vibrio parahaemolyticus</i>, H-NS represses virulence factors such as thermostable direct hemolysin (TDH), type III secretion systems (T3SS1/T3SS2), and type VI secretion systems (T6SS1/T6SS2). It also modulates swimming motility by activating polar flagellar genes while repressing swarming motility and lateral flagellar systems. Additionally, H-NS influences biofilm formation through regulation of exopolysaccharide synthesis and cyclic di-GMP (c-di-GMP) metabolism. Emerging evidence suggests cross-regulation with quorum sensing (QS) systems, though direct mechanistic insights into <i>V. parahaemolyticus</i> remain sparse. Furthermore, a recent study indicates H-NS roles extend to osmotic stress adaptation, such as regulating the ectoine biosynthetic pathway. This review synthesizes current knowledge on H-NS-mediated regulation in <i>V. parahaemolyticus</i> and offers new insights for future research.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 ","pages":"6503207"},"PeriodicalIF":1.9,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12909264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PANoptosis-Related Diagnostic Biomarkers in Non-Neovascular Age-Related Macular Degeneration: An Integrative Transcriptomic and Experimental Study.","authors":"Jiaming Li, Yirong Ma, Miao Hu, Qian Zhang, Anqi Wang, Qiuyu Tang, Qinshang Guo, Binglin Huang","doi":"10.1155/genr/8903808","DOIUrl":"10.1155/genr/8903808","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD), particularly its non-neovascular (dry) form, is a progressive retinal disorder that causes central vision loss and substantial impairment in daily life. Inflammation and immune dysregulation are recognized as core drivers of AMD, yet the contribution of PANoptosis, a form of programmed cell death that integrates pyroptosis, apoptosis, and necroptosis, remains unclear. In this study, we integrated human single-cell transcriptomic and bulk microarray datasets from the retina and retinal pigment epithelium-choroid to characterize PANoptosis-related transcriptional changes in dry AMD. Dimensionality reduction, cell-type annotation, and PANoptosis gene-set scoring revealed a distinct PANoptosis signature enriched in AMD, with particularly strong activation in myeloid populations. By combining differential expression analysis with machine learning-based feature selection, we identified four PANoptosis-related genes (PON2, BNIP3, EPHB6, and TPD52) that robustly distinguished AMD from control samples and were associated with an altered immune microenvironment. Genetic instrument analysis further suggested a positive association between TPD52 expression and AMD risk. At the cellular level, our data highlighted macrophages, especially pro-inflammatory M1-like macrophages, as key coordinators of PANoptosis-related pathways in dry AMD. To validate these findings in vivo, we used a sodium iodate-induced mouse model of dry AMD and observed significant dysregulation of PON2, BNIP3, EPHB6, and TPD52 in the retina by RT-qPCR, consistent with the human transcriptomic results and supporting their involvement in retinal degeneration and inflammation. Together, these findings implicate PANoptosis as an important and previously underappreciated component of dry AMD pathophysiology, define a four-gene PANoptosis-related signature with diagnostic potential, and suggest new molecular targets for therapeutic intervention.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 ","pages":"8903808"},"PeriodicalIF":1.9,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12905011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Structural Equation Modeling Combined With Post-GWAS Analysis Identifies Two Risk Gene Loci and Functionally Sensitive Genes Associated With Cardiac Conduction Block.","authors":"Tongyu Wang, Xinge Miao, Yunlong Xia","doi":"10.1155/genr/1063531","DOIUrl":"10.1155/genr/1063531","url":null,"abstract":"<p><strong>Background: </strong>Cardiac conduction disorders (CCDs) represent a broad spectrum of severe cardiovascular conditions associated with syncope and sudden cardiac death. Therefore, identification of reliable biomarkers is necessary to significantly improve the diagnostic accuracy and therapeutic outcomes of CCDs. This study analyzed GWAS summary datasets using a genomic structural equation model (Genomic-SEM), fine mapping, linkage disequilibrium score regression (LDSC), and two-sample Mendelian randomization (TSMR) analyses to identify genetic loci and genes associated with CCDs.</p><p><strong>Methods: </strong>GWAS summary datasets of European subjects were obtained from the GWAS Catalog and FinnGen databases. The GenomicSEM R package was used to construct a structural equation model to identify common latent factors influencing CCD progression. The Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA) platform was used to annotate the lead SNPs and candidate genes. Fine-mapping tools, such as SuSiE and FINEMAP, and Phenome-Wide Association Study (PheWAS) analysis were used to identify causal SNPs associated with CCDs. Transcriptome-Wide Association Study (TWAS) and Functional Summary Statistics (FOCUS) analyses were performed to identify CCD susceptibility genes. LDSC and TSMR were performed to determine causal relationships between the candidate risk genes and specific CCDs.</p><p><strong>Results: </strong>Newly explored CCD-associated leading SNPs (rs71208329 and rs112720315) were generated from genomic SEM and FUMA analyses. Fine-mapping and PheWAS analysis confirmed that rs112720315 was linked to nonischemic cardiomyopathy. TWAS, FUMA, and FOCUS analyses showed that five genes (<i>CCDC141</i>, <i>SCN10A</i>, <i>SH3PXD2A</i>, <i>FKBP7</i>, and <i>ESR2</i>) were associated with CCDs. The <i>APOL1</i> gene is associated with the risk of CCDs in African ancestry. TSMR and LDSC analyses further demonstrated that these genes were significantly associated with CCDs and were potential prediction biomarkers for CCDs.</p><p><strong>Conclusion: </strong>The novel genetic locus rs112720315 is significantly associated with the occurrence of CCDs. Biomarkers such as <i>CCDC141</i>, <i>SCN10A</i>, <i>ESR2</i>, <i>FKBP7</i>, <i>and SH3PXD2A</i> can predict a wide spectrum of CCDs. The <i>APOL1</i> gene is a specific marker for CCDs in African ancestry.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 ","pages":"1063531"},"PeriodicalIF":1.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12801132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell Transcriptomics and Integrated Bioinformatic Analysis Reveal Critical Biomarkers and Immune Infiltration Characteristics in Osteoarthritis.","authors":"Tiantian Gao, Chongshan Yang, Yikang Bi, Pingzhou Zou, Ma Wan, Shenghui Lan, Yuan Song, Yafeng Xu","doi":"10.1155/genr/1174568","DOIUrl":"10.1155/genr/1174568","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a complex, progressive joint disease characterized by cartilage degradation and inflammation. Traditional bulk tissue analyses have limited our understanding of the cellular diversity within OA tissues.</p><p><strong>Methods: </strong>This study employed scRNA-seq and integrated bioinformatic analyses to investigate the cellular composition and molecular pathways involved in OA. Publicly available datasets were analyzed to identify differentially expressed genes (DEGs) and enriched pathways. The genes, such as <i>NR4A2</i>, <i>BMP1</i>, and <i>AVPR1A</i>, were selected for further analysis. Molecular docking studies were conducted to explore the interaction with two identified compounds. Additionally, immune infiltration characteristics were analyzed using gene set variation analysis (GSVA) and correlation with key OA-associated genes.</p><p><strong>Results: </strong>We analyzed cartilage samples from OA and normal individuals (GSE220243) and identified eight distinct chondrocyte subpopulations, with significant pathway enrichment in TNF, TGF-β, and PI3K-Akt signaling pathways. Further differential gene expression analysis of GSE114007 identified 2247 genes, including 26 key OA-associated drug targets, such as <i>NR4A2</i>, <i>BMP1</i>, and <i>AVPR1A</i>, which demonstrated strong diagnostic potential (AUC > 0.70) across multiple cohorts. Immune infiltration analysis revealed significant correlations between these key genes and immune cell subsets, highlighting their roles in the inflammatory microenvironment of OA. Additionally, molecular docking studies suggested that bexarotene has a favorable binding affinity for NR4A2, BMP1, and AVPR1A, making it a promising therapeutic candidate.</p><p><strong>Conclusion: </strong>Our findings provide new insights into the molecular landscape of OA, offering valuable biomarkers and therapeutic targets for future OA interventions.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 ","pages":"1174568"},"PeriodicalIF":1.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12771611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylation Landscapes of Cartilage in Hip Osteoarthritis.","authors":"Ruiyang Jiang, Maochun Wang, Guihua Tan, Jie Lv, Xiaoyu Jin, Yuan Liu, Rui Wu, Dongquan Shi","doi":"10.1155/genr/5540232","DOIUrl":"10.1155/genr/5540232","url":null,"abstract":"<p><strong>Objective: </strong>To elucidate different methylation landscapes between cartilage of femoral neck fracture and preserved and damaged cartilages in hip osteoarthritis (OA).</p><p><strong>Methods: </strong>Genome-wide DNA methylation data were acquired from two data sets in GEO database (GSE63106 and GSE63695), which were based on Illumina HumanMethylation450 BeadChip arrays. A total of 63 hip samples were selected for further analysis, including 19 cartilages obtained from patients with femoral neck fracture, 14 preserved cartilages, and 30 damaged cartilages obtained from patients with OA. We identified the differential methylated positions (DMPs) and genes between different cartilage groups.</p><p><strong>Results: </strong>There were 116,750 DMPs and 51,200 DMPs identified in preserved and damaged cartilages compared to cartilage in femoral neck fracture, respectively, while there were no signals found between preserved and damaged cartilages. Gene ontology analysis showed that most of differential methylated genes were enriched in extracellular matrix and structure organization, collagen-containing extracellular matrix, and KEGG enrichment highlighted PI3K-AKT and AMPK signaling pathways, which were known to be crucial for the progression of OA. Further construction of protein-protein interaction networks with differential methylated genes elucidated molecular basis of the disease. Three hypermethylated genes (NOTCH1, GREM1, and DYSF) and three hypomethylated genes (HDAC4, S100A10, and RUNX1) were selected to detect the relative expression in different cartilages, and their expression was correlated with the methylation status within the genes.</p><p><strong>Conclusion: </strong>We demonstrated the differential methylated genes across the whole genome not only on preserved cartilage but also on damaged cartilage during OA. The molecular network highlighted the potential therapy targets which may be involved in the initiation or progression of the disease.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 ","pages":"5540232"},"PeriodicalIF":1.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12766398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compound Heterozygous ATM Variants Cause Adolescent-Onset Cerebellar and Extrapyramidal Disease Without Telangiectasia in a Consanguineous Pakistani Family.","authors":"Faiza Aslam, Weizhen Ji, Lauren Jeffries, Anant Wadhwa, Monica Konstantino, Muhammad Noman, Nigel S Bamford, Emily Mis, Saquib A Lakhani, Sadaf Naz","doi":"10.1155/genr/5644954","DOIUrl":"10.1155/genr/5644954","url":null,"abstract":"<p><p>Ataxia-telangiectasia (A-T) is a heterogeneous genetic disorder with a recessive mode of inheritance resulting from biallelic variants in the A-T mutated gene (ATM). Besides ataxia, the disorder involves compromised immunity and an increased risk of malignancies. We recruited a consanguineous Pakistani family with multiple individuals having adolescent-onset ataxia. Phenotyping and clinical testing were completed for the patients. DNA samples from multiple individuals were used for bidirectional exome sequencing at 100X coverage, and data were aligned to the hg19 genome assembly. Sanger sequencing was completed to confirm the segregation of the variants. Multiple sequence alignments of orthologous proteins from diverse species were performed using ClustalO to check the amino acid conservation. Patients in the family manifested gait and limb ataxia, postural instability, and dystonia. A known heterozygous pathogenic nonsense ATM variant, c.2413C > T, p.(Arg805Ter), in trans with a new unreported missense variant, c.8708C > T, p.(Pro2903Leu), was identified, which segregated with the disease. The missense variant affected an amino acid, which was conserved in evolution. Telangiectasia of the eyes and skin was absent in the affected individuals, which led to the initial misdiagnosis of the disease as cerebellar ataxia. There were no reports of malignancies in the family, and affected individuals were alive in their third and fourth decades of life. Thus, molecular analyses resulted in the reclassification of the disease as A-T, an example of reverse phenotyping. The study expands the phenotypic heterogeneity of A-T and extends the allelic spectrum of ATM variants.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 1","pages":"e5644954"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148328609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipids and Lipid-Lowering Drugs With Risk of Intervertebral Disc Degeneration: A Mendelian Randomization Study.","authors":"Aochen Xu, Jiabin Yuan","doi":"10.1155/genr/5378960","DOIUrl":"10.1155/genr/5378960","url":null,"abstract":"<p><p>This study examined whether circulating lipid traits and lipid-lowering drug targets are causally associated with intervertebral disc degeneration (IVDD) using a Mendelian randomization (MR) framework. We analyzed summary-level data from genome-wide association studies (GWASs) covering apolipoproteins, lipid parameters, and IVDD. Univariable analysis revealed that inherently elevated high-density lipoprotein cholesterol (HDL-C) correlated with reduced IVDD susceptibility. By contrast, low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A-I (Apoa-I), and apolipoprotein B (Apob) did not remain significant after Bonferroni correction. Upon adjusting for body mass index (BMI) in a multivariable framework, the protective link between HDL-C and IVDD held strong, whereas LDL-C, TG, and Apob remained nonsignificant. Summary data-based MR and drug-target MR analyses further suggested a significant association between NPC1L1 gene expression and IVDD susceptibility. Overall, these results highlight the potential involvement of lipid pathways in disc degeneration and justify further biological and clinical investigation.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 1","pages":"e5378960"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13420274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148619723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Genetic Diagnostic Markers for Systemic Lupus Erythematosus.","authors":"Qianqian Liu, Hairong Yang, Chunxiao Dang, Xingxing Song","doi":"10.1155/genr/7043184","DOIUrl":"10.1155/genr/7043184","url":null,"abstract":"<p><strong>Background: </strong>Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with poor treatment outcomes. While previous studies have indicated a genetic predisposition to SLE, the underlying mechanisms remain poorly understood.</p><p><strong>Objective: </strong>This study aimed to identify diagnostic targets with potential genetic associations to SLE by leveraging bioinformatics and the Mendelian randomization (MR) approach.</p><p><strong>Methods: </strong>Six datasets (GSE30153, GSE39088, GSE50635, GSE50772, GSE61635, and GSE110169) were obtained from the GEO database for differential expression analysis to identify differentially expressed genes (DEGs). Weighted gene coexpression network analysis (WGCNA) was then performed, and the most relevant module was intersected with the DEGs to identify candidate genes with potential diagnostic value. Subsequently, machine learning algorithms were applied to screen diagnostic genes, and their performance was evaluated using receiver operating characteristic (ROC) curves and confusion matrices. MR analysis was conducted to identify diagnostic genes with genetic associations. A protein-protein interaction (PPI) network was constructed to identify core genes. Finally, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis were performed.</p><p><strong>Results: </strong>Differential expression analysis identified 244 DEGs, and WGCNA revealed a highly relevant module. Intersecting this module with the DEGs produced 136 candidate genes. Machine learning algorithms and MR analysis further refined the selection, identifying five diagnostic genes: GBP1, IFI6, KLHDC8B, OAS3, and ZCCHC2, all of which were shown to be well-aligned with their respective drugs. The PPI network highlighted GBP1, IFI6, and OAS3 as core genes, which showed significant correlations with immune cell infiltration.</p><p><strong>Conclusions: </strong>Our study identified GBP1, IFI6, and OAS3 as core genes implicated in SLE pathogenesis, providing novel insights into its molecular mechanisms and potential therapeutic targets.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 1","pages":"e7043184"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the Impact of Deleterious Single-Nucleotide Polymorphisms in the p47ING1a Isoform of Human ING1 Gene.","authors":"Md Oliullah Rafi, Md Takim Sarker, Mohammad Ashik Sheikh, Sowmitro Das, Sajal Kumar Halder, Md Ashiqul Islam","doi":"10.1155/genr/2859448","DOIUrl":"10.1155/genr/2859448","url":null,"abstract":"<p><strong>Purpose: </strong>The p47ING1a isoform of the ING1 tumor suppressor regulates cellular senescence through Rb-dependent pathways via its plant homeodomain (PHD) zinc-finger, which recognizes the H3K4me3 histone mark. However, the mutational landscape of p47ING1a and the functional consequences of PHD-domain nonsynonymous single-nucleotide polymorphisms (nsSNPs) remain poorly characterized. This study aimed to identify and structurally evaluate the most deleterious nsSNPs in p47ING1a and clarify their potential role in disrupting ING1 tumor-suppressor activity.</p><p><strong>Methods: </strong>A total of 347 missense nsSNPs were retrieved from the NCBI dbSNP database and screened using 12 sequence-based computational tools. Variants consistently predicted as deleterious were further evaluated by I-Mutant stability analysis and ConSurf evolutionary conservation profiling. Three-dimensional structural modeling was performed using AlphaFold3, refined through GalaxyRefine, and validated by ERRAT, PROCHECK, and TM-align. Mutation-induced structural and binding effects were assessed using Missense3D, mCSM, and BeAtMuSiC. Post-translational modification sites were predicted via NetPhos 3.1, GPS 3.0, BDM-PUB, and NetOGlyc 4.0. Protein-protein interaction networks were constructed using STRING and Gene MANIA. Pan-cancer expression was analyzed through UALCAN and the Human Protein Atlas.</p><p><strong>Results: </strong>Twelve computational tools converged on six high-priority variants, namely, C358S, C374G, W378G, F379V, S382L, and R400P. All localized exclusively within the PHD zinc-finger domain, residues 353-402. All six mutations were consistently predicted to destabilize the p47ING1a protein across multiple stability analyses.</p><p><strong>Conclusions: </strong>Six nsSNPs in the PHD domain of p47ING1a are predicted to disrupt protein stability, H3K4me3 binding, and Sin3A/HDAC complex interactions, thereby impairing ING1 tumor-suppressor function. These findings provide a computational basis for prioritizing variants for experimental validation through site-directed mutagenesis, chromatin-binding assays, and structure-guided therapeutic targeting of the PHD-H3K4me3 interface.</p>","PeriodicalId":12778,"journal":{"name":"Genetics research","volume":"2026 1","pages":"e2859448"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}