Parkinson’s disease (PD) is a progressive degenerative neuronal disorder that involves the selective loss of dopaminergic neurons in the substantia nigra, resulting in severe motor and non-motor impairments. Key pathological hallmarks include the accumulation of misfolded α-synuclein and mitochondrial dysfunction. Emerging evidence indicates that innate immune signalling, particularly the cGAS-STING pathway, contributes to PD pathogenesis. It acts as a cytosolic DNA sensor; cGAS can recognise genomic instability or mitochondrial damage by generating an IFN-I response through STING activation. Persistent stimulation of the cGAS-STING pathway in microglia promotes chronic neuroinflammation and contributes to dopaminergic neuronal loss. Mitochondrial dysfunction, impaired DNA repair, and α-Synuclein aggregation may converge to sustain pathway activation, establishing a self-reinforcing cycle of inflammation and neurodegeneration. Understanding the interaction of cGAS-STING signalling, mitochondrial integrity, and protein aggregation offers important mechanistic insights into PD pathology. It suggests meaningful targets for disease-modifying therapeutic approaches for PD that address neuroinflammation and neuronal survival.
{"title":"cGAS-STING activation in Parkinson’s Disease: From mechanisms to Disease-Modifying therapeutic strategies","authors":"Jemimol Solomon , Snehashis Mandal , Khadga Raj Aran","doi":"10.1016/j.gene.2026.150000","DOIUrl":"10.1016/j.gene.2026.150000","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is a progressive degenerative neuronal disorder that involves the selective loss of dopaminergic neurons in the substantia nigra, resulting in severe motor and non-motor impairments. Key pathological hallmarks include the accumulation of misfolded α-synuclein and mitochondrial dysfunction. Emerging evidence indicates that innate immune signalling, particularly the cGAS-STING pathway, contributes to PD pathogenesis. It acts as a cytosolic DNA sensor; cGAS can recognise genomic instability or mitochondrial damage by generating an IFN-I response through STING activation. Persistent stimulation of the cGAS-STING pathway in microglia promotes chronic neuroinflammation and contributes to dopaminergic neuronal loss. Mitochondrial dysfunction, impaired DNA repair, and α-Synuclein aggregation may converge to sustain pathway activation, establishing a self-reinforcing cycle of inflammation and neurodegeneration. Understanding the interaction of cGAS-STING signalling, mitochondrial integrity, and protein aggregation offers important mechanistic insights into PD pathology. It suggests meaningful targets for disease-modifying therapeutic approaches for PD that address neuroinflammation and neuronal survival.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"985 ","pages":"Article 150000"},"PeriodicalIF":2.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1016/j.gene.2026.150001
Monica Gagliardi , Radha Procopio , Alessia Felicetti , Andrea Quattrone , Gennarina Arabia , Maurizio Morelli , Antonio Gambardella , Grazia Annesi , Aldo Quattrone
Background
Pathogenic variants in the LRRK2 gene are among the most common genetic causes of autosomal dominant Parkinson’s disease (PD). A recent study provided strong genetic and functional evidence supporting the pathogenicity of the rare missense variant p.L1795F (c.5385G > T), identified exclusively in individuals of European ancestry. However, its prevalence in Southern European populations remains unknown.
Objective
The aim of the study was to evaluate the frequency of the p.L1795F variant in a cohort of PD patients from Southern Italy.
Methods
We screened 300 unrelated PD patients using Sanger sequencing to detect the presence of the p.L1795F (c.5385G > T) variant in the LRRK2 gene.
Results
No carriers of the p.L1795F variant were identified in our Southern Italian cohort.
Conclusion
These findings suggest that the p.L1795F variant may have very low or undetectable frequency in the Southern Italian population. Our results highlight the importance of including underrepresented geographic regions in genetic screening efforts for PD to better understand the population-specific distribution of pathogenic variants.
{"title":"No evidence for the LRRK2 p.L1795F variant in a Southern Italian cohort with Parkinson’s disease","authors":"Monica Gagliardi , Radha Procopio , Alessia Felicetti , Andrea Quattrone , Gennarina Arabia , Maurizio Morelli , Antonio Gambardella , Grazia Annesi , Aldo Quattrone","doi":"10.1016/j.gene.2026.150001","DOIUrl":"10.1016/j.gene.2026.150001","url":null,"abstract":"<div><h3>Background</h3><div>Pathogenic variants in the <em>LRRK2</em> gene are among the most common genetic causes of autosomal dominant Parkinson’s disease (PD). A recent study provided strong genetic and functional evidence supporting the pathogenicity of the rare missense variant p.L1795F (c.5385G > T), identified exclusively in individuals of European ancestry. However, its prevalence in Southern European populations remains unknown.</div></div><div><h3>Objective</h3><div>The aim of the study was to evaluate the frequency of the p.L1795F variant in a cohort of PD patients from Southern Italy.</div></div><div><h3>Methods</h3><div>We screened 300 unrelated PD patients using Sanger sequencing to detect the presence of the p.L1795F (c.5385G > T) variant in the <em>LRRK2</em> gene.</div></div><div><h3>Results</h3><div>No carriers of the p.L1795F variant were identified in our Southern Italian cohort.</div></div><div><h3>Conclusion</h3><div>These findings suggest that the p.L1795F variant may have very low or undetectable frequency in the Southern Italian population. Our results highlight the importance of including underrepresented geographic regions in genetic screening efforts for PD to better understand the population-specific distribution of pathogenic variants.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"984 ","pages":"Article 150001"},"PeriodicalIF":2.4,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-31DOI: 10.1016/j.gene.2025.149991
Fanfan Wang , Jian Liu , Yanyan Fang , Yang Li , Xueni Cheng , Shengfeng Liu
Background
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and multi-organ damage. While existing therapies alleviate symptoms, they are accompanied by significant adverse effects. Fibroblast-like synoviocytes (FLS) drive RA progression through inflammation-coagulation interactions, necessitating safer multitarget drugs. Jianpi Wenyang Tongluo Prescription-Wuwei Wentong Chubi Capsule (WWT), a traditional Chinese medicine formula targeting the “cold-dampness obstruction syndrome” in RA, has demonstrated clinical efficacy, yet its mechanism remains unclear.
Aim of the study
To investigate the therapeutic effects of WWT on adjuvant-induced arthritis (AA) rats with cold-dampness syndrome and explore its underlying mechanisms in regulating inflammation-coagulation balance and organ protection.
Materials and methods
AA rats with cold-dampness syndrome were established using Freund’s complete adjuvant (FCA) and a climate chamber, and treated with WWT (low/medium/high doses). Synovial pathology, organ function, inflammatory, and coagulation parameters were evaluated. Molecular docking, protein–protein interaction (PPI) networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were employed to identify key targets, with Western blot (WB) and immunofluorescence used to validate JAK2/STAT3 pathway activation. A coculture model of peripheral blood mononuclear cells (PBMCs) and FLS from RA patients was constructed for in vitro validation.
Results
In AA rats, WWT dose-dependently decreased pro-inflammatory cytokines (IL-6, IL-17) and pro-coagulant factors (PAF, FDP), while increasing anti-inflammatory cytokine IL-10 and anticoagulant factor PGI2 (P < 0.01). WWT reversed synovial mitochondrial vacuolation and protected liver and kidney function. Bioinformatics analysis and molecular docking revealed JAK2/STAT3 as the core target, with wogonin and icariin stably binding to JAK2 (ΔG = -8.2/-7.7 kcal/mol) and STAT3 (ΔG = -7.9/-9.9 kcal/mol). WWT rescued inflammation and hypercoagulation induced by the JAK2/STAT3 activator coumermycin A1. In vitro, WWT-containing serum inhibited the proliferation of cocultured RA-PBMCs and FLS and the secretion of pro-inflammatory and pro-coagulant factors by blocking JAK2/STAT3 and STAT3 nuclear translocation.
Conclusions
WWT alleviates RA progression by restoring inflammation-coagulation balance and protecting multi-organ function through inhibition of the JAK2/STAT3 pathway. This study integrates traditional Chinese medicine theory with molecular pathological mechanisms, providing a scientific basis for WWT as a multitarget therapeutic for RA.
背景：类风湿性关节炎（RA）是一种以滑膜增生和多器官损害为特征的慢性自身免疫性疾病。虽然现有的治疗方法减轻了症状，但它们伴随着显著的不良反应。纤维母细胞样滑膜细胞（FLS）通过炎症-凝血相互作用驱动RA进展，需要更安全的多靶点药物。健脾温阳通络方-武味温通除痹胶囊是一种治疗类风湿痹证的中药方剂，临床疗效较好，但其作用机制尚不清楚。研究目的：观察水灵汤对佐剂性关节炎（AA）大鼠寒湿证的治疗作用，并探讨其调节炎症-凝血平衡和器官保护的机制。材料和方法：采用弗氏完全佐剂（FCA）和气候室建立寒湿证AA大鼠，并给予低/中/高剂量WWT治疗。评估滑膜病理、器官功能、炎症和凝血参数。利用分子对接、蛋白-蛋白相互作用（PPI）网络和京都基因与基因组百科全书（KEGG）富集分析确定关键靶点，利用Western blot （WB）和免疫荧光验证JAK2/STAT3通路的激活。建立RA患者外周血单个核细胞（PBMCs）与FLS共培养模型进行体外验证。结果：在AA大鼠中，WWT剂量依赖性地降低了促炎因子（IL-6、IL-17）和促凝因子（PAF、FDP），同时增加了抗炎因子IL-10和抗凝因子PGI2 （P ）。结论：WWT通过抑制JAK2/STAT3通路，恢复了炎症-凝平衡，保护了多器官功能，从而减轻了RA的进展。本研究将中医理论与分子病理机制相结合，为WWT多靶点治疗类风湿性关节炎提供科学依据。
{"title":"Revealing the dual mechanisms of Wuwei Wentong Chubi Capsule in alleviating rheumatoid arthritis: synergistic anti-inflammatory and anti-coagulant effects","authors":"Fanfan Wang , Jian Liu , Yanyan Fang , Yang Li , Xueni Cheng , Shengfeng Liu","doi":"10.1016/j.gene.2025.149991","DOIUrl":"10.1016/j.gene.2025.149991","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and multi-organ damage. While existing therapies alleviate symptoms, they are accompanied by significant adverse effects. Fibroblast-like synoviocytes (FLS) drive RA progression through inflammation-coagulation interactions, necessitating safer multitarget drugs. Jianpi Wenyang Tongluo Prescription-Wuwei Wentong Chubi Capsule (WWT), a traditional Chinese medicine formula targeting the “cold-dampness obstruction syndrome” in RA, has demonstrated clinical efficacy, yet its mechanism remains unclear.</div></div><div><h3>Aim of the study</h3><div>To investigate the therapeutic effects of WWT on adjuvant-induced arthritis (AA) rats with cold-dampness syndrome and explore its underlying mechanisms in regulating inflammation-coagulation balance and organ protection.</div></div><div><h3>Materials and methods</h3><div>AA rats with cold-dampness syndrome were established using Freund’s complete adjuvant (FCA) and a climate chamber, and treated with WWT (low/medium/high doses). Synovial pathology, organ function, inflammatory, and coagulation parameters were evaluated. Molecular docking, protein–protein interaction (PPI) networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were employed to identify key targets, with Western blot (WB) and immunofluorescence used to validate JAK2/STAT3 pathway activation. A coculture model of peripheral blood mononuclear cells (PBMCs) and FLS from RA patients was constructed for in vitro validation.</div></div><div><h3>Results</h3><div>In AA rats, WWT dose-dependently decreased pro-inflammatory cytokines (IL-6, IL-17) and pro-coagulant factors (PAF, FDP), while increasing anti-inflammatory cytokine IL-10 and anticoagulant factor PGI2 (P < 0.01). WWT reversed synovial mitochondrial vacuolation and protected liver and kidney function. Bioinformatics analysis and molecular docking revealed JAK2/STAT3 as the core target, with wogonin and icariin stably binding to JAK2 (ΔG = -8.2/-7.7 kcal/mol) and STAT3 (ΔG = -7.9/-9.9 kcal/mol). WWT rescued inflammation and hypercoagulation induced by the JAK2/STAT3 activator coumermycin A1. In vitro, WWT-containing serum inhibited the proliferation of cocultured RA-PBMCs and FLS and the secretion of pro-inflammatory and pro-coagulant factors by blocking JAK2/STAT3 and STAT3 nuclear translocation.</div></div><div><h3>Conclusions</h3><div>WWT alleviates RA progression by restoring inflammation-coagulation balance and protecting multi-organ function through inhibition of the JAK2/STAT3 pathway. This study integrates traditional Chinese medicine theory with molecular pathological mechanisms, providing a scientific basis for WWT as a multitarget therapeutic for RA.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149991"},"PeriodicalIF":2.4,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.gene.2025.149988
Chenlu Tang, Xiaofeng Jin
Endometrial cancer (EC) is one of the three most common malignancies of the female reproductive system, with its global incidence and disease-related mortality continuing to rise. Cervical cancer (CC), also known as uterine cervical cancer, refers to cancer occurring in the cervix. Despite the development of various therapeutic strategies, patient prognosis and survival rates remain poor due to high rates of metastasis and recurrence. Ubiquitination denotes the process by which ubiquitin is covalently attached to target proteins, while deubiquitinases (DUBs) catalyze the reverse process. Accumulating evidence indicates that dysregulation of deubiquitination plays significant roles in the pathogenesis and progression of both EC and CC. This review systematically summarizes recent research advances in DUBs, outlining their intrinsic characteristics, classification, catalytic mechanisms, and modes of activity regulation. Furthermore, it explores the potential mechanisms by which DUB dysregulation contributes to endometrial and cervical carcinogenesis. Additionally, we present the successful application of DUB inhibitors in the treatment of malignancies and provide an analysis of the current research status regarding targeted therapies for EC and CC.
{"title":"Deubiquitinating enzymes in endometrial cancer and cervical cancer","authors":"Chenlu Tang, Xiaofeng Jin","doi":"10.1016/j.gene.2025.149988","DOIUrl":"10.1016/j.gene.2025.149988","url":null,"abstract":"<div><div>Endometrial cancer (EC) is one of the three most common malignancies of the female reproductive system, with its global incidence and disease-related mortality continuing to rise. Cervical cancer (CC), also known as uterine cervical cancer, refers to cancer occurring in the cervix. Despite the development of various therapeutic strategies, patient prognosis and survival rates remain poor due to high rates of metastasis and recurrence. Ubiquitination denotes the process by which ubiquitin is covalently attached to target proteins, while deubiquitinases (DUBs) catalyze the reverse process. Accumulating evidence indicates that dysregulation of deubiquitination plays significant roles in the pathogenesis and progression of both EC and CC. This review systematically summarizes recent research advances in DUBs, outlining their intrinsic characteristics, classification, catalytic mechanisms, and modes of activity regulation. Furthermore, it explores the potential mechanisms by which DUB dysregulation contributes to endometrial and cervical carcinogenesis. Additionally, we present the successful application of DUB inhibitors in the treatment of malignancies and provide an analysis of the current research status regarding targeted therapies for EC and CC.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149988"},"PeriodicalIF":2.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.gene.2025.149990
Qiyue Ma , Ningna Wang , Kaikai Qiao , Kun Luo , Chenglong Zhao , Jiaxuan Yan , Shuli Fan , Junkang Rong , Qifeng Ma
Male reproductive development is fundamental to the life cycle of flowering plants, culminating in seed production. Aberrations in anther development frequently lead to male sterility, yet the underlying molecular mechanisms in upland cotton (Gossypium hirsutum) remain largely uncharacterized. The R2R3-MYB family of transcription factors are known key regulators of diverse developmental processes, including male fertility in several model species. Here, we identify and functionally characterize GhMYB35, an R2R3-MYB transcription factor that plays an essential role in cotton anther development. CRISPR/Cas9-mediated knockout of GhMYB35 resulted in complete male sterility, with mutants (ghmyb35) exhibiting indehiscent anthers, shorter filaments, and a total absence of viable pollen. Expression analyses reveal that GhMYB35 is predominantly expressed in anthers, with peak expression of its A- and D-subgenome homoeologs occurring at developmental stage 7. Subcellular localization results show that both GhMYB35_A and GhMYB35_D are nuclear-localized transcription factors. Furthermore, the total absence of GhMYB35 leads to pollen abortion and subsequent anther collapse without dehiscence. Collectively, our findings establish GhMYB35 as a critical regulator of anther maturation, thereby elucidating a key component of the molecular network governing male fertility in cotton.
{"title":"The R2R3-MYB transcription factor GhMYB35 governs anther development and pollen viability in upland cotton","authors":"Qiyue Ma , Ningna Wang , Kaikai Qiao , Kun Luo , Chenglong Zhao , Jiaxuan Yan , Shuli Fan , Junkang Rong , Qifeng Ma","doi":"10.1016/j.gene.2025.149990","DOIUrl":"10.1016/j.gene.2025.149990","url":null,"abstract":"<div><div>Male reproductive development is fundamental to the life cycle of flowering plants, culminating in seed production. Aberrations in anther development frequently lead to male sterility, yet the underlying molecular mechanisms in upland cotton (<em>Gossypium hirsutum</em>) remain largely uncharacterized. The R2R3-MYB family of transcription factors are known key regulators of diverse developmental processes, including male fertility in several model species. Here, we identify and functionally characterize <em>GhMYB35</em>, an R2R3-MYB transcription factor that plays an essential role in cotton anther development. CRISPR/Cas9-mediated knockout of <em>GhMYB35</em> resulted in complete male sterility, with mutants (<em>ghmyb35</em>) exhibiting indehiscent anthers, shorter filaments, and a total absence of viable pollen. Expression analyses reveal that <em>GhMYB35</em> is predominantly expressed in anthers, with peak expression of its A- and D-subgenome homoeologs occurring at developmental stage 7. Subcellular localization results show that both<!--> <em>GhMYB35_A</em> <!-->and<!--> <em>GhMYB35_D</em> <!-->are nuclear-localized transcription factors. Furthermore, the total absence of GhMYB35 leads to pollen abortion and subsequent anther collapse without dehiscence. Collectively, our findings establish <em>GhMYB35</em> as a critical regulator of anther maturation, thereby elucidating a key component of the molecular network governing male fertility in cotton.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"984 ","pages":"Article 149990"},"PeriodicalIF":2.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case–control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in RAD51, XRCC2, XRCC3 (HRR), and XRCC4, LIG4 (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP–SNP interactions, while in silico tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for RAD51 (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15–7.06; p = 0.049), and the CT genotype of LIG4 (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11–3.07; p = 0.0097). Conversely, CT genotype carriers of XRCC3 (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32–0.75; p = 0.003). XRCC2 and XRCC4 showed no significant associations. However, XRCC2 variants correlated with tumor grade and menopausal status, and XRCC3 with tumor histology. MDR analysis revealed strong interactions between XRCC3 and RAD51, followed by combinations involving XRCC2, suggesting synergistic HRR gene effects. In silico predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, RAD51 and LIG4 polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.
低外显率DNA修复基因（DRGs）对卵巢癌（OC）风险的贡献仍然知之甚少。同源重组修复（HRR）和非同源末端连接（NHEJ）途径基因的变异可能影响基因组稳定性并调节OC易感性。这项基于人群的病例对照研究（474名受试者，237名OC患者和237名对照）评估了RAD51、XRCC2、XRCC3 （HRR）和XRCC4、LIG4 （NHEJ）的多态性，以评估它们在OC易感性中的作用。使用PCR-RFLP进行基因分型，并进行logistic回归估计风险关联。多因素降维（MDR）分析检查了SNP-SNP相互作用，而在硅工具和静电表面作图预测了结构和功能效应。在RAD51 （rs1801320）中观察到显著的相关性，其中突变CC基因型个体的OC风险增加2.8倍（OR = 2.85; 95% CI = 1.15-7.06; p = 0.049），而CT基因型LIG4 （rs1805388）的风险增加1.85倍（OR = 1.85; 95% CI = 1.11-3.07; p = 0.0097）。相反，CT基因型携带者XRCC3 （rs861539）表现出较低的OC风险（OR = 0.49; 95% CI = 0.32-0.75; p = 0.003）。XRCC2和XRCC4无显著相关性。然而，XRCC2变异与肿瘤分级和绝经状态相关，XRCC3与肿瘤组织学相关。MDR分析显示，XRCC3与RAD51之间存在较强的相互作用，其次是涉及XRCC2的组合，提示HRR基因的协同作用。计算机预测表明，XRCC2 R188H具有不稳定性，XRCC3 T241M具有混合效应，而LIG4 T9I具有稳定性。总的来说，RAD51和LIG4多态性可能与南印度妇女的OC易感性有关。需要更大规模、多中心的研究来验证这些发现，并探索其作为卵巢癌预测生物标志物的潜力。
{"title":"Integrated case–control and in silico analysis of DNA double-strand break repair gene variants (RAD51, XRCC2, XRCC3, XRCC4, and LIG4) for ovarian cancer susceptibility","authors":"Harshavardhani Canchi Sistla , Arun Seshachalam , Krishna Kumar Rathnam , Taruna Rajagopal , Srikanth Talluri , Subaranjana Saravanaguru Vasanthi , Nageswara Rao Dunna","doi":"10.1016/j.gene.2025.149989","DOIUrl":"10.1016/j.gene.2025.149989","url":null,"abstract":"<div><div>The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case–control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in <em>RAD51, XRCC2, XRCC3</em> (HRR), and <em>XRCC4, LIG4</em> (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP–SNP interactions, while <em>in silico</em> tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for <em>RAD51</em> (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15–7.06; p = 0.049), and the CT genotype of <em>LIG4</em> (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11–3.07; p = 0.0097). Conversely, CT genotype carriers of <em>XRCC3</em> (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32–0.75; p = 0.003). <em>XRCC2</em> and <em>XRCC4</em> showed no significant associations. However, <em>XRCC2</em> variants correlated with tumor grade and menopausal status, and <em>XRCC3</em> with tumor histology. MDR analysis revealed strong interactions between <em>XRCC3</em> and <em>RAD51</em>, followed by combinations involving <em>XRCC2</em>, suggesting synergistic HRR gene effects. <em>In silico</em> predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, <em>RAD51</em> and <em>LIG4</em> polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149989"},"PeriodicalIF":2.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The DOT1L gene encodes a histone lysine methyltransferase that has the distinctive characteristic of being composed of a DOT1 catalytic domain that targets lysine 79 of the core globular domain of histone H3. DOT1L missense variants have recently been implicated in an autosomal dominant inheritance syndrome with developmental delay and congenital anomalies in postnatal cohorts. We report the twenty-sixth patient with this disorder.
Methods
Trio genome sequencing (GS) was performed in a patient with developmental delay.
Results
Clinical examination showed a predominant global developmental delay affecting language, with cerebral abnormalities visible on magnetic resonance imaging, hypotonia, and ophthalmological and musculoskeletal abnormalities. GS revealed a de novo heterozygous missense variant in exon 3 of DOT1L (c.161C > T; p.(Ala54Val)), which is reported for the first time as the cause of developmental delay and congenital anomalies.
Discussion
Among the 26 reported patients, 23 have missense variants, two have truncating variants, and one has an in-frame deletion. The mode of transmission is predominantly de novo. Current studies indicate multiple pathogenic mechanisms underlying DOT1L-related disorder, including both gain-of-function and loss-of-function effects, underscoring the complexity of the disease etiology. Although the gene exhibits intolerance to loss-of-function variants, a considerable number of truncating variants are observed in control populations, suggesting incomplete penetrance and heterogeneity in the phenotypic expression of DOT1L-associated disorder. No phenotype-genotype correlation could be established. Among reported patients, including ours, the most consistent clinical manifestations are global developmental delay, predominantly affecting language and behavior, and possibly distinctive facial features.
{"title":"Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants","authors":"Aurélien Caux , Florence Jobic , Boris Keren , Alexis Billes , Virginie Magry , Anaïs L’Haridon , Walaa Darwiche , Guillaume Jedraszak , Gilles Morin","doi":"10.1016/j.gene.2025.149987","DOIUrl":"10.1016/j.gene.2025.149987","url":null,"abstract":"<div><h3>Introduction</h3><div>The <em>DOT1L</em> gene encodes a histone lysine methyltransferase that has the distinctive characteristic of being composed of a DOT1 catalytic domain that targets lysine 79 of the core globular domain of histone H3. <em>DOT1L</em> missense variants have recently been implicated in an autosomal dominant inheritance syndrome with developmental delay and congenital anomalies in postnatal cohorts. We report the twenty-sixth patient with this disorder.</div></div><div><h3>Methods</h3><div>Trio genome sequencing (GS) was performed in a patient with developmental delay.</div></div><div><h3>Results</h3><div>Clinical examination showed a predominant global developmental delay affecting language, with cerebral abnormalities visible on magnetic resonance imaging, hypotonia, and ophthalmological and musculoskeletal abnormalities. GS revealed a <em>de novo</em> heterozygous missense variant in exon 3 of <em>DOT1L</em> (c.161C > T; p.(Ala54Val)), which is reported for the first time as the cause of developmental delay and congenital anomalies.</div></div><div><h3>Discussion</h3><div>Among the 26 reported patients, 23 have missense variants, two have truncating variants, and one has an in-frame deletion. The mode of transmission is predominantly <em>de novo</em>. Current studies indicate multiple pathogenic mechanisms underlying DOT1L-related disorder, including both gain-of-function and loss-of-function effects, underscoring the complexity of the disease etiology. Although the gene exhibits intolerance to loss-of-function variants, a considerable number of truncating variants are observed in control populations, suggesting incomplete penetrance and heterogeneity in the phenotypic expression of DOT1L-associated disorder. No phenotype-genotype correlation could be established. Among reported patients, including ours, the most consistent clinical manifestations are global developmental delay, predominantly affecting language and behavior, and possibly distinctive facial features.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149987"},"PeriodicalIF":2.4,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145870010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.gene.2025.149985
Shengting Zhang , Sha Zhao , Lijuan Liu , Huili Tao , Jinmei Chai , Yani Ju , Chengqian Dong , Yunlin Wei
Enterococcus faecalis is a facultative anaerobe often associated with persistent infections. It can rapidly adapt and grow in environments with varying oxygen levels (aerobic, microaerobic, hypoxic, and anaerobic), making it a major pathogen responsible for refractory periapical periodontitis. The study investigated the fatty acid content and its variations in Enterococcus faecalis strain YN771 under different oxygen concentrations. Subsequently, transcriptomics and metabolomics were combined to characterize the underlying mechanisms. The results showed that YN771 exhibited altered transcriptional and metabolomic profiles when exposed to different oxygen levels. These changes highlighted the oxygen adaptation and regulatory mechanisms of YN771, including sulfur metabolism, glutathione metabolism, glutamate metabolism, pyruvate metabolism, tricarboxylic acid cycle, peptidoglycan biosynthesis, and fatty acid biosynthesis regulation. Additionally, the study examined the expression changes of virulence factors in YN771 under different oxygen levels, which are also regulated by quorum sensing. This research comprehensively explores the metabolic regulation of YN771 under varying oxygen levels and analyzes key enzyme genes and virulence factors involved in its oxygen response regulation, providing mechanistic insights for developing therapeutic strategies against this notorious pathogen.
{"title":"Transcriptomic and metabolomic insights into the oxygen adaptation mechanisms of Enterococcus faecalis YN771","authors":"Shengting Zhang , Sha Zhao , Lijuan Liu , Huili Tao , Jinmei Chai , Yani Ju , Chengqian Dong , Yunlin Wei","doi":"10.1016/j.gene.2025.149985","DOIUrl":"10.1016/j.gene.2025.149985","url":null,"abstract":"<div><div><em>Enterococcus faecalis</em> is a facultative anaerobe often associated with persistent infections. It can rapidly adapt and grow in environments with varying oxygen levels (aerobic, microaerobic, hypoxic, and anaerobic), making it a major pathogen responsible for refractory periapical periodontitis. The study investigated the fatty acid content and its variations in <em>Enterococcus faecalis</em> strain YN771 under different oxygen concentrations. Subsequently, transcriptomics and metabolomics were combined to characterize the underlying mechanisms. The results showed that YN771 exhibited altered transcriptional and metabolomic profiles when exposed to different oxygen levels. These changes highlighted the oxygen adaptation and regulatory mechanisms of YN771, including sulfur metabolism, glutathione metabolism, glutamate metabolism, pyruvate metabolism, tricarboxylic acid cycle, peptidoglycan biosynthesis, and fatty acid biosynthesis regulation. Additionally, the study examined the expression changes of virulence factors in YN771 under different oxygen levels, which are also regulated by quorum sensing. This research comprehensively explores the metabolic regulation of YN771 under varying oxygen levels and analyzes key enzyme genes and virulence factors involved in its oxygen response regulation, providing mechanistic insights for developing therapeutic strategies against this notorious pathogen.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"982 ","pages":"Article 149985"},"PeriodicalIF":2.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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