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No evidence for the LRRK2 p.L1795F variant in a Southern Italian cohort with Parkinson’s disease 没有证据表明LRRK2 p.L1795F变异在意大利南部帕金森病患者中存在。
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-20 Epub Date: 2026-01-05 DOI: 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.
背景:LRRK2基因的致病性变异是常染色体显性帕金森病(PD)最常见的遗传原因之一。最近的一项研究提供了强有力的遗传和功能证据,支持罕见的错义变异p.L1795F (c.5385G > T)的致病性,该变异仅在欧洲血统的个体中发现。然而,其在南欧人群中的流行程度尚不清楚。目的:该研究的目的是评估p.L1795F变异在意大利南部PD患者队列中的频率。方法:我们使用Sanger测序技术筛选了300名不相关的PD患者,检测LRRK2基因中p.L1795F (c.5385G > T)变体的存在。结果:在我们的意大利南部队列中未发现p.L1795F变异携带者。结论:这些发现表明p.L1795F变异在意大利南部人群中的频率可能非常低或无法检测到。我们的研究结果强调了将代表性不足的地理区域纳入PD遗传筛查工作的重要性,以更好地了解致病变异的人群特异性分布。
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引用次数: 0
Insights into the role of the two-component system pfeS/pfeR in Vibrio harveyi adaptation to host fish blood. 双组分系统pfe /pfeR在哈维弧菌对宿主鱼血的适应中的作用
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-19 DOI: 10.1016/j.gene.2026.150116
Huirong Xiang, Zhe Zhang, Qingpi Yan, Ziyan Du, Linmin Zhao, Weihong Zhao, Yingxue Qin

Host environments are complex and highly dynamic for bacterial pathogens, requiring rapid and precise response and adaptation for successful systemic infection. In this study, RNA-Seq was used to investigate the transcriptional response of Vibrio harveyi TS-628 during adaptation to yellow grouper (Epinephelus awoara) blood. A total of 1,273 genes were differentially expressed, accounting for 28.35% of the total gene complement, indicating a highly significant metabolic reprogramming of V. harveyi during host adaptation. Genes encoding two-component systems (TCSs) were prominently enriched among the differentially expressed genes (DEGs). Notably, the pfeS/pfeR TCS was consistently up-regulated during adaptation to host blood, mucus, and muscle, suggesting its core role in the host adaptation. Subsequent knockdown of pfeS or pfeR did not affect bacterial growth but altered the expression of iron uptake-related genes, implying a regulatory role of the TCS in maintaining iron homeostasis. Furthermore, both pfeS972-RNAi and pfeR492-RNAi strains displayed significantly reduced motility, chemotaxis, and biofilm formation, indicating that the pfeS/pfeR system coordinates multiple adaptive traits essential for host colonization. Blood exposure significantly induced chemotaxis and biofilm formation in the wild-type strain, but this inducibility was lost in the knockdown strains, suggesting that the pfeS/pfeR system may function in environmental signal sensing. In conclusion, we hypothesize that during the early stages of infection, pfeS/pfeR mediates metabolic reprogramming in response to environmental cues, thereby regulating iron homeostasis and virulence-related behaviors to promote bacterial adaptation to the host environment and preparing for further dissemination.

对于细菌病原体来说,宿主环境是复杂和高度动态的,需要快速和精确的反应和适应才能成功的全身感染。本研究采用RNA-Seq技术研究了哈维弧菌TS-628对黄石斑鱼(Epinephelus awoara)血液的适应转录反应。共有1273个基因差异表达,占总基因补体的28.35%,表明哈维伊弧菌在宿主适应过程中进行了高度显著的代谢重编程。编码双组分系统(TCSs)的基因在差异表达基因(DEGs)中显著富集。值得注意的是,在对宿主血液、粘液和肌肉的适应过程中,pfe /pfeR TCS持续上调,表明其在宿主适应中的核心作用。随后敲低pfe或pfeR并不影响细菌生长,但改变了铁摄取相关基因的表达,这意味着TCS在维持铁稳态中起调节作用。此外,pfeS972-RNAi和pfeR492-RNAi菌株的移动性、趋化性和生物膜形成均显著降低,表明pfeS/pfeR系统协调了宿主定植所必需的多种适应特性。在野生型菌株中,血液暴露显著诱导趋化性和生物膜形成,但在基因敲低的菌株中,这种诱导作用消失,这表明pfe /pfeR系统可能在环境信号感知中起作用。总之,我们假设在感染的早期阶段,pfe /pfeR介导代谢重编程以响应环境信号,从而调节铁稳态和毒力相关行为,促进细菌对宿主环境的适应并为进一步传播做准备。
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引用次数: 0
Deubiquitination-driven adaptive programs in hepatocellular carcinoma: The emerging role of USP22 in hypoxia, metabolic rewiring, and drug resistance. 肝细胞癌中去泛素化驱动的适应性程序:USP22在缺氧、代谢重新布线和耐药性中的新作用
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-17 DOI: 10.1016/j.gene.2026.150107
Haohao Mei, Ni Yan

Hepatocellular carcinoma (HCC) is characterized by profound phenotypic plasticity and limited therapeutic durability. Despite the availability of tyrosine kinase inhibitors, chemotherapy, and immune checkpoint inhibitors, most patients eventually develop resistance, often in the absence of clear genetic alterations. This highlights the importance of non-genetic, adaptive mechanisms that enable tumor cells to survive therapeutic and microenvironmental stress. Deubiquitination has emerged as a critical regulatory layer in stress adaptation, yet its role in orchestrating coordinated resistance programs remains underappreciated. Ubiquitin-specific protease 22 (USP22), originally characterized as a component of the SAGA transcriptional complex, is increasingly recognized as a central regulator of adaptive reprogramming in HCC. In this review, we synthesize recent mechanistic and translational studies demonstrating how USP22 integrates hypoxia tolerance, metabolic rewiring, cancer stemness, immune evasion, and drug resistance into a unified adaptive network. We highlight the role of USP22-centered positive feedback loops in converting transient stress signals into stable, drug-tolerant states, thereby driving non-genetic resistance to targeted therapy, chemotherapy, and immunotherapy. Finally, we discuss emerging therapeutic strategies that exploit USP22 dependency through combination and timing-aware interventions, as well as the potential of USP22 as a biomarker for identifying highly adaptive, treatment-refractory HCC. Collectively, these insights position USP22 as a network stabilizer of malignant adaptation and a promising target for overcoming therapeutic resistance in hepatocellular carcinoma.

肝细胞癌(HCC)具有深刻的表型可塑性和有限的治疗持久性。尽管有酪氨酸激酶抑制剂、化疗和免疫检查点抑制剂,但大多数患者最终会产生耐药性,通常没有明显的遗传改变。这突出了非遗传、适应性机制的重要性,使肿瘤细胞能够在治疗和微环境压力下存活。去泛素化已成为应激适应的关键调控层,但其在协调抗性程序中的作用仍未得到充分认识。泛素特异性蛋白酶22 (USP22),最初被认为是SAGA转录复合体的一个组成部分,越来越被认为是HCC中适应性重编程的中心调节因子。在这篇综述中,我们综合了最近的机制和转化研究,证明了USP22如何将缺氧耐受性,代谢重新布线,癌症干细胞,免疫逃避和耐药性整合到一个统一的适应性网络中。我们强调了以usp22为中心的正反馈回路在将瞬态应激信号转化为稳定的耐药状态中的作用,从而驱动对靶向治疗、化疗和免疫治疗的非遗传抗性。最后,我们讨论了利用USP22依赖性的新兴治疗策略,通过联合和时间意识干预,以及USP22作为识别高适应性、治疗难治性HCC的生物标志物的潜力。总的来说,这些见解将USP22定位为恶性适应的网络稳定剂和克服肝细胞癌治疗耐药的有希望的靶点。
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引用次数: 0
De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature. 先天性贫血和早发性肾病的新生SEC61A1突变:病例报告和文献回顾
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-16 DOI: 10.1016/j.gene.2026.150106
Linqing Zhong, Juan Ding, Mingsheng Ma, Changyan Wang, Juan Xiao, Min Wei, Shan Jian

Background: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic disorder characterized by tubular damage and interstitial fibrosis, with inescapable progression to end-stage renal disease. SEC61A1-related ADTKD has long been neglected and underrecognized because of its rarity, insidious onset and variable clinical manifestations.

Results: A 13-year-old boy was referred to the pediatric nephrology clinic due to renal insufficiency, which had been found unexpectedly while visiting the hospital because of growth retardation. He had normocytic normochromic anemia since early childhood and was recently found to have agranulocytosis. The evaluation suggested elevated serum creatinine, hyperuricemia, bland urinary sediment, the absence of proteinuria, and renal cysts. A novel de novo heterozygous missense variant in SEC61A1, Ser71Pro, was found. So far fifteen patients with SEC61A1-related ADTKD have been reported, most of whom presented with early-onset chronic kidney disease and hyperuricemia. The extrarenal features included growth retardation, hematological abnormalities, cognitive impairment, and immunological abnormalities. There is no specific treatment for the SEC61A1-related ADTKD. Most reported patients survived to adulthood with supportive treatment.

Conclusions: This is the first case of SEC61A1-related ADTKD of Chinese origin, extending its phenotype and mutation spectrum. The diagnosis of SEC61A1-related ADTKD should be considered in patients with early-onset or familial chronic kidney disease, hematological abnormalities and growth retardation, and mutation analysis of SEC61A1 is needed.

背景:常染色体显性小管间质肾病(ADTKD)是一种罕见的遗传性疾病,以小管损伤和间质纤维化为特征,不可避免地发展为终末期肾病。sec61a1相关ADTKD因其罕见、发病隐匿、临床表现多变,长期以来被忽视和未被充分认识。结果:一名13岁男孩因生长发育迟缓,在就诊时意外发现肾功能不全,转诊至小儿肾脏科门诊。他从小就患有正红细胞性贫血,最近发现有粒细胞缺乏症。评估提示血清肌酐升高、高尿酸血症、淡性尿沉渣、无蛋白尿和肾囊肿。在SEC61A1中发现了一种新的杂合错义变体Ser71Pro。到目前为止,已经报道了15例与sec61a1相关的ADTKD患者,其中大多数表现为早发性慢性肾病和高尿酸血症。肾外特征包括生长迟缓、血液异常、认知障碍和免疫异常。目前尚无针对sec61a1相关ADTKD的特异性治疗方法。大多数报告的患者通过支持性治疗存活到成年。结论:这是中国首例与sec61a1相关的ADTKD,扩展了其表型和突变谱。对于早发性或家族性慢性肾病、血液学异常、生长迟缓的患者,应考虑SEC61A1相关ADTKD的诊断,需要对SEC61A1进行突变分析。
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引用次数: 0
Revealing the dual mechanisms of Wuwei Wentong Chubi Capsule in alleviating rheumatoid arthritis: synergistic anti-inflammatory and anti-coagulant effects 揭示五味温通除痹胶囊缓解类风湿关节炎的双重机制:协同抗炎和抗凝血作用。
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-15 Epub Date: 2025-12-31 DOI: 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 ,&nbsp;Jian Liu ,&nbsp;Yanyan Fang ,&nbsp;Yang Li ,&nbsp;Xueni Cheng ,&nbsp;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 &lt; 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":"2026-03-15","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}
引用次数: 0
SR protein kinase FoSrk1 integrates RNA splicing, carbon metabolism, and virulence in Fusarium oxysporum f. sp. cubense SR蛋白激酶FoSrk1整合了尖孢镰刀菌的RNA剪接、碳代谢和毒力。
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-15 Epub Date: 2025-12-12 DOI: 10.1016/j.gene.2025.149954
Han Ouyang , Jiayi Peng , Zhouqi Huang , Yicong Huang , Yinglan Wen , Yuan Xu , Yu Long , Huijiao Lin , Qiyan Fu , Zhaojian Ding
Fusarium oxysporum f. sp. cubense (Foc), the causal agent of banana Fusarium wilt, is one of the most destructive plant pathogens worldwide. However, the molecular mechanisms that integrate fungal growth, metabolism, and virulence remain poorly understood. This study identifies and functionally characterizes FoSrk1, a serine/arginine-rich protein kinase (SRPK), in Foc. Deletion of FoSrk1 markedly impaired vegetative growth, reduced aerial mycelium formation and conidiation, and significantly attenuated virulence toward banana plantlets. The mutant also exhibited compromised utilization of diverse carbon sources, accompanied by altered expression of 32 genes involved in carbon metabolism. Complementation with the wild-type FoSrk1 allele restored normal growth and pathogenicity, confirming the gene’s essential role. Transcriptomic analyses revealed that loss of FoSrk1 altered the expression of 2,500 genes and was associated with changes in 37 alternative splicing events, predominantly intron retention, affecting transcripts linked to protein metabolism, ribosome biogenesis, and redox processes. Moreover, several virulence-associated genes encoding ABC transporters, cytochrome P450 enzymes, and hydrophobins were downregulated in the FoSrk1-deficient strain. These findings suggest that FoSrk1 acts as an important regulator that couples RNA processing with metabolic and pathogenic pathways and is required for normal fungal development and virulence. This study provides new insight into the molecular basis of pathogenic adaptation and identifies FoSrk1 as a potential target for antifungal intervention strategies.
香蕉枯萎病病原菌Fusarium oxysporum f. sp. cubense (Foc)是世界上最具破坏性的植物病原体之一。然而,整合真菌生长、代谢和毒力的分子机制仍然知之甚少。本研究鉴定并功能表征了FoSrk1,一种在Foc中富含丝氨酸/精氨酸的蛋白激酶(SRPK)。缺失FoSrk1显著损害香蕉植株的营养生长,减少气生菌丝的形成和分生,并显著降低对香蕉植株的毒力。该突变体还表现出对不同碳源的利用受损,并伴有涉及碳代谢的32个基因的表达改变。与野生型FoSrk1等位基因的互补恢复了正常的生长和致病性,证实了该基因的重要作用。转录组学分析显示,FoSrk1的缺失改变了2500个基因的表达,并与37个可变剪接事件的变化有关,主要是内含子保留,影响与蛋白质代谢、核糖体生物发生和氧化还原过程相关的转录本。此外,编码ABC转运蛋白、细胞色素P450酶和疏水蛋白的几个毒力相关基因在fosrk1缺陷菌株中下调。这些发现表明,FoSrk1是一个重要的调节因子,将RNA加工与代谢和致病途径结合起来,是正常真菌发育和毒力所必需的。该研究为致病适应的分子基础提供了新的见解,并确定了FoSrk1作为抗真菌干预策略的潜在靶点。
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引用次数: 0
Deubiquitinating enzymes in endometrial cancer and cervical cancer 去泛素酶在子宫内膜癌和宫颈癌中的作用。
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-15 Epub Date: 2025-12-30 DOI: 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.
子宫内膜癌(EC)是女性生殖系统最常见的三种恶性肿瘤之一,其全球发病率和与疾病相关的死亡率持续上升。宫颈癌(CC),也称为子宫癌,是指发生在子宫颈的癌症。尽管发展了各种治疗策略,但由于转移和复发率高,患者预后和生存率仍然很差。泛素化是指泛素与靶蛋白共价结合的过程,而去泛素酶(DUBs)则催化相反的过程。越来越多的证据表明,去泛素化失调在EC和CC的发病和发展中都起着重要的作用。本文系统地综述了DUBs的研究进展,概述了它们的内在特征、分类、催化机制和活性调节模式。此外,它还探讨了DUB失调导致子宫内膜癌和宫颈癌发生的潜在机制。此外,我们介绍了DUB抑制剂在恶性肿瘤治疗中的成功应用,并分析了目前针对EC和CC的靶向治疗的研究现状。
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引用次数: 0
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 DNA双链断裂修复基因变异(RAD51、XRCC2、XRCC3、XRCC4和LIG4)对卵巢癌易感性的综合病例对照和计算机分析
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-15 Epub Date: 2025-12-30 DOI: 10.1016/j.gene.2025.149989
Harshavardhani Canchi Sistla , Arun Seshachalam , Krishna Kumar Rathnam , Taruna Rajagopal , Srikanth Talluri , Subaranjana Saravanaguru Vasanthi , Nageswara Rao Dunna
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。
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引用次数: 0
Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants 与DOT1L变异相关的神经发育综合征病例报告及文献综述
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-15 Epub Date: 2025-12-29 DOI: 10.1016/j.gene.2025.149987
Aurélien Caux , Florence Jobic , Boris Keren , Alexis Billes , Virginie Magry , Anaïs L’Haridon , Walaa Darwiche , Guillaume Jedraszak , Gilles Morin

Introduction

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.
DOT1L基因编码一种组蛋白赖氨酸甲基转移酶,该酶具有由DOT1催化结构域组成的独特特征,该结构域靶向组蛋白H3核心球状结构域的赖氨酸79。DOT1L错义变异体最近被认为与常染色体显性遗传综合征有关,并发发育迟缓和出生后先天性异常。我们报告第26例此病患者。方法对1例发育迟缓患者进行基因组测序(GS)。结果临床检查显示主要的整体发育迟缓影响语言,磁共振成像显示大脑异常,张力低下,眼科和肌肉骨骼异常。GS在DOT1L的外显子3 (c.161C >; T; p.(Ala54Val))中发现了一个全新的杂合错义变异(c.161C >; T; p.(Ala54Val)),这是首次报道的发育迟缓和先天性异常的原因。在26例报告的患者中,23例有错义变异体,2例有截断变异体,1例有帧内缺失。传播方式主要是新生。目前的研究表明,dot1l相关疾病的多种致病机制,包括功能获得和功能丧失效应,强调了疾病病因的复杂性。尽管该基因表现出对功能缺失变异的不耐受,但在对照人群中观察到相当数量的截断变异,这表明dot1l相关疾病的表型表达存在不完全外显性和异质性。表型与基因型之间不存在相关性。在报告的患者中,包括我们的患者,最一致的临床表现是全面发育迟缓,主要影响语言和行为,并可能有明显的面部特征。
{"title":"Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants","authors":"Aurélien Caux ,&nbsp;Florence Jobic ,&nbsp;Boris Keren ,&nbsp;Alexis Billes ,&nbsp;Virginie Magry ,&nbsp;Anaïs L’Haridon ,&nbsp;Walaa Darwiche ,&nbsp;Guillaume Jedraszak ,&nbsp;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 &gt; 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":"2026-03-15","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}
引用次数: 0
Syntaphilin inhibits glioma invasion via modulating mitochondria redistribution and shapes the immune microenvironment: A potential prognostic biomarker. Syntaphilin通过调节线粒体再分布和塑造免疫微环境抑制胶质瘤侵袭:一个潜在的预后生物标志物。
IF 2.4 3区 生物学 Q2 GENETICS & HEREDITY Pub Date : 2026-03-14 DOI: 10.1016/j.gene.2026.150105
Hui Tian, Xuan Chen, Mingbin Si, Wenzhe Xu

Background: Glioma remains a lethal brain malignancy with a dismal prognosis. Syntaphilin (SNPH), a mitochondrial anchoring protein, shows emerging relevance in cancer biology. This study investigates the diagnostic and prognostic potential of SNPH, while elucidatingits functional mechanisms in glioma progression.

Methods: The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Genotype-Tissue Expression (GTEx) and Human Protein Atlas (HPA) were utilized to systematically analyze SNPH, including its differential transcriptional and translational expression, survival correlation, functional enrichment, and immune microenvironment in glioma. Subsequently, the effects of SNPH on cell migration, invasion, mitochondria distribution, epithelial-mesenchymal transition, focal adhesion (FA) maturation and FA kinase (FAK) signaling were validated via in vitro.

Results: SNPH expression was markedlydownregulatedin glioma (P < 0.001), demonstratinghigh diagnostic potential for glioma detection (area under the curve = 0.819). Clinically, decreasedSNPH levelswere associatedwith aggressive features(WHO grade G4, glioblastoma subtype) (both P < 0.001), unfavorable molecular characteristics[IDH-wildtype (P = 0.005), 1p19q non-codeletion (P < 0.001)], and significantlypredicted worse overall survival (P < 0.001). Functional enrichment analyses revealed SNPH's involvementin immunomodulation and migration-related processes, particularly FA pathway and FAK signaling. Immune profiling indicated an inverse correlation between SNPH expression and the abundance of T helper cells, macrophages and neutrophils. In vitro, SNPH overexpression suppressed invasion and epithelial-mesenchymal transition. Mechanistically, it promoted perinuclear mitochondrial clustering, attenuated FA maturation, FAK phosphorylation and RhoA/Rac1/Cdc42 expression.

Conclusion: These findings establish SNPH as a novel diagnostic/prognostic biomarker and metastasis suppressor in glioma, functioning through mitochondrial repositioning-mediated inhibition of migration pathways.

背景:神经胶质瘤是一种预后不佳的致死性脑恶性肿瘤。Syntaphilin (SNPH)是一种线粒体锚定蛋白,在癌症生物学中显示出新的相关性。本研究探讨了SNPH的诊断和预后潜力,同时阐明了其在胶质瘤进展中的功能机制。方法:利用肿瘤基因组图谱(TCGA)、中国胶质瘤基因组图谱(CGGA)、基因型-组织表达图谱(GTEx)和人蛋白图谱(HPA)对SNPH在胶质瘤中的差异转录和翻译表达、存活相关性、功能富集、免疫微环境等进行系统分析。随后,通过体外实验验证了SNPH对细胞迁移、侵袭、线粒体分布、上皮-间质转化、局灶黏附(FA)成熟和FA激酶(FAK)信号传导的影响。结果:SNPH在胶质瘤中的表达明显下调(P )。结论:这些发现表明SNPH在胶质瘤中是一种新的诊断/预后生物标志物和转移抑制因子,通过线粒体重新定位介导的迁移途径抑制其功能。
{"title":"Syntaphilin inhibits glioma invasion via modulating mitochondria redistribution and shapes the immune microenvironment: A potential prognostic biomarker.","authors":"Hui Tian, Xuan Chen, Mingbin Si, Wenzhe Xu","doi":"10.1016/j.gene.2026.150105","DOIUrl":"10.1016/j.gene.2026.150105","url":null,"abstract":"<p><strong>Background: </strong>Glioma remains a lethal brain malignancy with a dismal prognosis. Syntaphilin (SNPH), a mitochondrial anchoring protein, shows emerging relevance in cancer biology. This study investigates the diagnostic and prognostic potential of SNPH, while elucidatingits functional mechanisms in glioma progression.</p><p><strong>Methods: </strong>The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Genotype-Tissue Expression (GTEx) and Human Protein Atlas (HPA) were utilized to systematically analyze SNPH, including its differential transcriptional and translational expression, survival correlation, functional enrichment, and immune microenvironment in glioma. Subsequently, the effects of SNPH on cell migration, invasion, mitochondria distribution, epithelial-mesenchymal transition, focal adhesion (FA) maturation and FA kinase (FAK) signaling were validated via in vitro.</p><p><strong>Results: </strong>SNPH expression was markedlydownregulatedin glioma (P < 0.001), demonstratinghigh diagnostic potential for glioma detection (area under the curve = 0.819). Clinically, decreasedSNPH levelswere associatedwith aggressive features(WHO grade G4, glioblastoma subtype) (both P < 0.001), unfavorable molecular characteristics[IDH-wildtype (P = 0.005), 1p19q non-codeletion (P < 0.001)], and significantlypredicted worse overall survival (P < 0.001). Functional enrichment analyses revealed SNPH's involvementin immunomodulation and migration-related processes, particularly FA pathway and FAK signaling. Immune profiling indicated an inverse correlation between SNPH expression and the abundance of T helper cells, macrophages and neutrophils. In vitro, SNPH overexpression suppressed invasion and epithelial-mesenchymal transition. Mechanistically, it promoted perinuclear mitochondrial clustering, attenuated FA maturation, FAK phosphorylation and RhoA/Rac1/Cdc42 expression.</p><p><strong>Conclusion: </strong>These findings establish SNPH as a novel diagnostic/prognostic biomarker and metastasis suppressor in glioma, functioning through mitochondrial repositioning-mediated inhibition of migration pathways.</p>","PeriodicalId":12499,"journal":{"name":"Gene","volume":" ","pages":"150105"},"PeriodicalIF":2.4,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467570","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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