Human molecular genetics最新文献

CRISPR-Cas9-driven antigen conversion of clinically relevant blood group systems.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-04-02 DOI: 10.1093/hmg/ddaf040

Yelena Boccacci, Nellie Dumont, Yannick Doyon, Josée Laganière

{"title":"CRISPR-Cas9-driven antigen conversion of clinically relevant blood group systems.","authors":"Yelena Boccacci, Nellie Dumont, Yannick Doyon, Josée Laganière","doi":"10.1093/hmg/ddaf040","DOIUrl":"https://doi.org/10.1093/hmg/ddaf040","url":null,"abstract":"The common practice of blood transfusion entirely relies on blood donations from the population. Ensuring blood group compatibility between a donor and a recipient is paramount to prevent critical adverse reactions. Finding compatible blood can be challenging given the high diversity of blood group antigens, especially for chronically transfused patients at higher risk of alloimmunization owing to repeated exposures to foreign RBCs. In addition, due to the immunogenicity of the ABO blood group and the highly polymorphic nature of the Rhesus (Rh) system, they both remain of prime importance in transfusion medicine. Cultured red blood cells (cRBCs) may eventually provide an alternative for blood donations-at least in some circumstances. Combining cRBCs with blood group gene editing could broaden transfusion accessibility by making antigen expression compatible with rare phenotypes, thus meeting the needs of more patients. Starting from mobilized, erythroid-primed hematopoietic stem and progenitor cells (HSPCs), we used virus- and selection-free, CRISPR-Cas9-mediated knockouts to produce erythroid cells devoid of AB and Rh antigen. The approach yielded almost complete conversion to O- and RhNull phenotypes, as determined by standard hemagglutination and flow cytometry analyses. Combined with robust cRBC protocols, these clinically relevant phenotypic changes could eventually expand the accessibility of blood transfusion for specific and unmet clinical needs.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Knockdown of TSP-4 alleviates MI/RI-induced myocardial injury and improves brain inflammation by enhancing blood-brain barrier stability.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-29 DOI: 10.1093/hmg/ddaf037

Jiahao Feng, Yanfeng Lu, Haoyu Wu, Wangge Ma, Yong Zhang, Ning Guo

{"title":"Knockdown of TSP-4 alleviates MI/RI-induced myocardial injury and improves brain inflammation by enhancing blood-brain barrier stability.","authors":"Jiahao Feng, Yanfeng Lu, Haoyu Wu, Wangge Ma, Yong Zhang, Ning Guo","doi":"10.1093/hmg/ddaf037","DOIUrl":"https://doi.org/10.1093/hmg/ddaf037","url":null,"abstract":"Myocardial ischemia-reperfusion injury (MI/RI) not only affects cardiac function but also has significant implications for neurological health, potentially leading to cognitive and behavioral impairments. At present, the regulatory role of thrombospondin-4 (TSP-4) in MI/RI has not been reported. A MI/RI mouse model was constructed, and primary cardiomyocytes were isolated. An MI/RI in vitro cell model was constructed using hypoxia/reoxygenation (H/R)-induced H9c2 cells. Haematoxylin and eosin and Masson staining were performed to observe morphological differentiation and fibrosis in myocardial tissues. Evans blue staining was used to analyse blood-brain barrier (BBB) permeability. Behavioural experiments were conducted to assess the learning and cognitive functions of mice. The results showed that the expression of TSP-4 was significantly increased in the blood of patients with ischemic cardiomyopathy and in the myocardial tissue of MI/RI mice. Functional studies showed that TSP knockdown alleviated H/R-induced H9c2 cell injury, including inflammation and oxidative stress. Importantly, interference with TSP-4 alleviated myocardial dysfunction in MI/RI mice. Mechanistically, by improving BBB stability, TSP-4 knockdown alleviated neuronal injury and the inflammatory response in mice induced by MI/RI. Further research found that silencing TSP-4 alleviated cognitive impairment and improved learning in MI/RI mice. Knockdown of TSP-4 improved MI/RI-induced functional cardiomyocyte injury. In addition, by enhancing BBB stability, TSP-4 silencing alleviated MI/RI-induced neurological injury and cognitive impairment in mice.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expression of Concern: Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-28 DOI: 10.1093/hmg/ddaf042

引用次数: 0

The role of CSNK1A1 and its de novo mutations in infantile spasms syndrome.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-28 DOI: 10.1093/hmg/ddaf030

Decheng Ren, Zhenxi Yang, Juan Hu, Lei Ji, Yan Bi, Fan Yuan, Yang Yan, Jing Peng, Keyi Li, Ke Yang, Liangjie Liu, Xiao Mao, Yingying Luo, Yanlin Wang, Guang He, Kai Li, Ying Peng

{"title":"The role of CSNK1A1 and its de novo mutations in infantile spasms syndrome.","authors":"Decheng Ren, Zhenxi Yang, Juan Hu, Lei Ji, Yan Bi, Fan Yuan, Yang Yan, Jing Peng, Keyi Li, Ke Yang, Liangjie Liu, Xiao Mao, Yingying Luo, Yanlin Wang, Guang He, Kai Li, Ying Peng","doi":"10.1093/hmg/ddaf030","DOIUrl":"https://doi.org/10.1093/hmg/ddaf030","url":null,"abstract":"Infantile spasms syndrome (ISS) is an early-onset epileptic encephalopathy characterized by uncontrollable seizures, severe electroencephalogram abnormalities, as well as delayed cognitive and behavioral development. Independent studies have shown that a variety of genes are involved in ISS and genetic factors play a critical role in its pathogenesis. Here we report two de novo mutations in the casein kinase 1 isoform alpha (CSNK1A1) gene which underlie severe epilepsy with similar clinical presentation in two patients. The identified variants are one missense mutation c.646G > C (p.Ala216Pro, Mut) in NM_001025105.3 and one deletion c.599_604delACATAC (p.His200_Ile201del, Del). In vitro analyses indicated that the Mut causes significant decreases in both mRNA and protein expression, while the Del demonstrated no significant impact on gene expression level. However, co-immunoprecipitation studies have shown that both mutations lead to reduced interactions between CSNK1A1 and β-catenin, resulting in excessive intracellular β-catenin and aberrant expression of several downstream genes. Compared with the wild type (WT), the EdU positive rates in cells transfected with Mut plasmid or Del plasmid were both elevated. Wnt/β-catenin signaling pathway is crucial to neurogenesis. An abnormal rise in β-catenin level has been utilized to generate genetic models for ISS. Our results not only elucidate the role of a novel candidate gene CSNK1A1 in the pathology of ISS, but also provide further evidence for the findings that mediating Wnt/β-catenin signaling is a potential mechanism causing ISS.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expression of Concern: Naturally occurring germline and tumor-associated mutations within the ATP-binding motifs of PTEN lead to oxidative damage of DNA associated with decreased nuclear p53. 表达关切：PTEN 的 ATP 结合基序中自然发生的种系突变和肿瘤相关突变会导致 DNA 氧化损伤，并导致核 p53 降低。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-28 DOI: 10.1093/hmg/ddaf041

引用次数: 0

New insights into tumor microenvironment and HPV integrations in cervical cancer pathogenesis revealed by single-cell transcriptome data. 单细胞转录组数据揭示宫颈癌发病机制中肿瘤微环境和 HPV 整合的新见解。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-27 DOI: 10.1093/hmg/ddaf027

Xi Zeng, Fang Peng, Ziying Wang, Qiuli Teng, Ying Sha, Ross Ka-Kit Leung, L A I Koon Chi Christopher, Guoliang Li, Xiaoyuan Huang, Shitong Lin

{"title":"New insights into tumor microenvironment and HPV integrations in cervical cancer pathogenesis revealed by single-cell transcriptome data.","authors":"Xi Zeng, Fang Peng, Ziying Wang, Qiuli Teng, Ying Sha, Ross Ka-Kit Leung, L A I Koon Chi Christopher, Guoliang Li, Xiaoyuan Huang, Shitong Lin","doi":"10.1093/hmg/ddaf027","DOIUrl":"https://doi.org/10.1093/hmg/ddaf027","url":null,"abstract":"HPV infection is common among women and can result in serious illnesses. This research utilizes single-cell RNA-sequencing (scRNA-seq) to study the connection between cellular heterogeneity and HPV integrations in cervical histopathology. scRNA-seq was used to examine heterogeneity among normal patients and those in three disease stages: high-grade squamous intraepithelial lesions (HSIL), microinvasive carcinoma (MIC), and cervical squamous epithelium carcinoma cancer (CSCC) tissues. A method was developed to identify HPV integration events from scRNA-seq data. Our results indicated an increase in squamous epithelial cells and a decrease in columnar epithelial cells as the disease progressed from normal to CSCC. We discovered HPV genes that were differentially expressed across normal patients and those in the three disease stages. Notably, HPV integration events were more common in squamous epithelial cells at the single-cell level. The ratio of HPV-integrated cells increased as the disease progressed from normal tissue to CSCC, eventually stabilizing. Several genes, such as EGR1, S100A11, S100A8, KRT5, RPL34, ATP1B1, RPS4X and EEF2, were frequently integrated by HPV across patients. In contrast, genes like PAN3, BABAM2, SPEN, TCIM-SIRLNT, TEX41-PABPC1P2 and KCNV1-LINC01608 showed frequent integration events across cells. KRT5, ATP1B1, RPS4X, PAN3 and SPEN were novel recurrent HPV-integrated genes we observed at the patient or cell level in this study. Additionally, we found that HPV genes from various HPV types exhibited integration preferences in various samples and disease stages. This provides a valuable insight into the mechanism of HPV-induced cervical cancer from a single-cell standpoint, highlighting its clinical relevance.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Dual faces of itaconate and its derivatives: exploring diverse biological functions in immunity and infectious diseases.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-26 DOI: 10.1093/hmg/ddae177

Cecilie Poulsen, Dominic G Roy, David Olagnier

引用次数: 0

Expression of Concern: The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation.

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-24 DOI: 10.1093/hmg/ddaf039

引用次数: 0

Rare and common genetic variants underlying the risk of Hirschsprung's disease. 罕见和常见的基因变异是先天性巨结肠病的潜在风险。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-20 DOI: 10.1093/hmg/ddae205

Jun Xiao, Chenzhao Feng, Tianqi Zhu, Xuan Zhang, Xuyong Chen, Zejian Li, Jingyi You, Qiong Wang, Didi Zhuansun, Xinyao Meng, Jing Wang, Lei Xiang, Xiaosi Yu, Bingyan Zhou, Weibing Tang, Jinfa Tou, Yi Wang, Heying Yang, Lei Yu, Yuanmei Liu, Xuewu Jiang, Hongxia Ren, Mei Yu, Qi Chen, Qiang Yin, Xiang Liu, Zhilin Xu, Dianming Wu, Donghai Yu, Xiaojuan Wu, Jixin Yang, Bo Xiong, Feng Chen, Xingjie Hao, Jiexiong Feng

{"title":"Rare and common genetic variants underlying the risk of Hirschsprung's disease.","authors":"Jun Xiao, Chenzhao Feng, Tianqi Zhu, Xuan Zhang, Xuyong Chen, Zejian Li, Jingyi You, Qiong Wang, Didi Zhuansun, Xinyao Meng, Jing Wang, Lei Xiang, Xiaosi Yu, Bingyan Zhou, Weibing Tang, Jinfa Tou, Yi Wang, Heying Yang, Lei Yu, Yuanmei Liu, Xuewu Jiang, Hongxia Ren, Mei Yu, Qi Chen, Qiang Yin, Xiang Liu, Zhilin Xu, Dianming Wu, Donghai Yu, Xiaojuan Wu, Jixin Yang, Bo Xiong, Feng Chen, Xingjie Hao, Jiexiong Feng","doi":"10.1093/hmg/ddae205","DOIUrl":"10.1093/hmg/ddae205","url":null,"abstract":"Hirschsprung's disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"586-598"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expression variation of long noncoding RNAs in dopaminergic cells-derived from stem cells and their MPP+ induced PD models. 长链非编码rna在干细胞来源的多巴胺能细胞及其MPP+诱导PD模型中的表达变化

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-03-20 DOI: 10.1093/hmg/ddae192

Setareh Behrouzi Abady Pamsary, Fariba Esmaeili, Fariba Dehghanian, Mohammad Hadi Bahadori

{"title":"Expression variation of long noncoding RNAs in dopaminergic cells-derived from stem cells and their MPP+ induced PD models.","authors":"Setareh Behrouzi Abady Pamsary, Fariba Esmaeili, Fariba Dehghanian, Mohammad Hadi Bahadori","doi":"10.1093/hmg/ddae192","DOIUrl":"10.1093/hmg/ddae192","url":null,"abstract":"Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder characterized by the progressive loss of nigrostriatal dopaminergic neurons (DA) which can be caused by environmental and genetic factors. lncRNAs have emerged as an important regulatory layer in neurodegenerative disorders, including PD. In this study, we investigated and validated lncRNAs that may serve as diagnostic or therapeutic targets for PD. Key genes associated with midbrain and DA cells were screened by differential gene expression analysis on GSE213100 dataset and candidate lncRNAs were selected for further examination. P19 cells were differentiated into DA cells and received treatment with MPP+ to induce PD-like cytotoxic events, which were confirmed by light microscopy, RT-qPCR, immunofluorescence and flow cytometry. Then, the cells were used to investigate the changes of lncRNAs Malat1, Norad, Snhg1 and Meg3. Here we found that the neuronal phenotype was mainly observed on the 12th day of differentiation and the number of DA markers significantly decreased in PD model cells compared with the control group. Moreover, the expression levels of Meg3, Norad, and Snhg1 were decreased by MPP+ whereas Malat1 level was noticeably higher in MPP+ cells compared to DA cells and the control group. In conclusion, the expression level of lncRNAs was able to show a significant difference between differentiated dopaminergic cells and their Parkinsonian model, thereby improving our understanding of the molecular pathogenesis of PD.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"599-610"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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