Human molecular genetics最新文献

{"title":"The role of CNBP in brain atrophy and its targeting in myotonic dystrophy type 2.","authors":"Katherine Jennings, Diana Lindquist, Ankita Poonia, Benedikt Schoser, Christiane Schneider-Gold, Nikolai A Timchenko, Lubov Timchenko","doi":"10.1093/hmg/ddaf002","DOIUrl":"https://doi.org/10.1093/hmg/ddaf002","url":null,"abstract":"<p><p>Myotonic Dystrophy type 2 (DM2) is a multisystem disease affecting many tissues, including skeletal muscle, heart, and brain. DM2 is caused by unstable expansion of CCTG repeats in an intron 1 of a gene coding for cellular nuclear binding protein (CNBP). The expanded CCTG repeats cause DM2 pathology due to the accumulation of RNA CCUG repeats, which affect RNA processing in patients' cells. We have previously shown that mutant CCUG repeats reduce CNBP protein in DM2 patients. Reducing Cnbp in Cnbp KO mouse model causes late skeletal muscle atrophy. In this study, we examined if the reduction of Cnbp affects the Central Nervous System (CNS). MRI and DTI analyses showed that total brain volume and grey matter are reduced in Cnbp KO mice, while mean, radial and axonal brain diffusivity is increased. The morphological changes in the brains of Cnbp KO mice are accompanied by reduced stereotypic behavior, anxiety and neuromotor defects. These findings suggest that the reduction of CNBP contributes to CNS pathology in DM2. Since CNBP stability is regulated by pAMPK-dependent phosphorylation, we examined protein levels of pAMPK in DM2 cells and found that the active pAMPK is reduced in DM2. Interaction of CNBP with pAMPK and stability of CNBP protein are also decreased in DM2. Our data show that a small molecule AMPK activator A769662 corrects CNBP stability and normalizes CNBP targets in DM2 fibroblasts. Thus, activators of AMPK could potentially be developed as therapeutics to correct CNBP and reduce muscle and brain atrophies in DM2.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978306","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}

{"title":"UBE2S, downregulated by miR-152-3p, facilitates prostate cancer progression through the PTEN-mediated AKT/mTOR pathway.","authors":"Chunhui Wang, Gang Zhang, Ying Jiang, Guochang Bao, Chunsheng Li","doi":"10.1093/hmg/ddaf004","DOIUrl":"https://doi.org/10.1093/hmg/ddaf004","url":null,"abstract":"<p><strong>Objectives: </strong>In recent years, the incidence and mortality rates of prostate cancer (PCa) have still not been significantly reduced and the mechanisms of tumor onset and progression are still not fully understood. The pathogenic mechanisms and upstream regulation of UBE2S expression in prostate cancer have not been elucidated.</p><p><strong>Methods: </strong>Here, we performed bioinformatic analysis of public databases to reveal the expression of UBE2S in PCa and its association with Gleason score, tumor staging, biochemical recurrence, and survival. Subsequently, the effect of UBE2S on the proliferation and invasive capacity of PCa cells was explored. Next, miR-152-3p was identified to bind to the 3'-UTR of UBE2S mRNA and down-regulated in PCa through luciferase reporter assays. Dual immunofluorescence assay and co-immunoprecipitation assays were performed to verify the regulatory role of UBE2S on PTEN. Finally, the molecular mechanism of UBE2S regulation of PCa progression was further confirmed by rescue experiments and in vivo nude mouse subcutaneous transplantation tumor experiments.</p><p><strong>Results: </strong>UBE2S expression was upregulated in PCa and correlated with patient Gleason score, TNM stage, biochemical recurrence, and disease-free survival. miR-152-3p regulated UBE2S expression in PCa by binding to the UBE2S mRNA 3'-UTR. Mechanistically, UBE2S combines with PTEN and ubiquitinates it, leading to PTEN degradation and ultimately promoting PCa progression via the AKT/mTOR signaling pathway.</p><p><strong>Conclusions: </strong>UBE2S, down-regulated by miR-152-3p, plays an important role in the onset and progression of PCa through the PTEN-mediated Akt/mTOR pathway and may become a new diagnostic marker and therapeutic target for PCa.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978307","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}

{"title":"Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction.","authors":"Xia Zhao, Haifeng Zhang, Yangyang Liu, Li Li, Haitao Wei","doi":"10.1093/hmg/ddae193","DOIUrl":"https://doi.org/10.1093/hmg/ddae193","url":null,"abstract":"<p><p>Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978305","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}

{"title":"Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.","authors":"Rachael A Wyatt, Aqfan Jamaluddin, Vinesh Mistry, Caitlin Quinn, Caroline M Gorvin","doi":"10.1093/hmg/ddaf005","DOIUrl":"https://doi.org/10.1093/hmg/ddaf005","url":null,"abstract":"<p><p>The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed at hypothalamic neurons that has an important role in appetite suppression and food intake. Mutations in MC4R are the most common cause of monogenic obesity and can affect multiple signaling pathways including Gs-cAMP, Gq, ERK1/2, β-arrestin recruitment, internalization and cell surface expression. The melanocortin-2 receptor accessory protein 2 (MRAP2), is a single-pass transmembrane protein that interacts with and regulates signaling by MC4R. Variants in MRAP2 have also been identified in overweight and obese individuals. However, functional studies that have only measured the effect of MRAP2 variants on MC4R-mediated cAMP signaling have produced inconsistent findings and most do not reduce MC4R function. Here we investigated the effect of twelve of these previously reported MRAP2 variants and showed that all variants that have been identified in overweight or obese individuals impair MC4R function. When expressed at equal concentrations, seven MRAP2 variants impaired MC4R-mediated cAMP signaling, while nine variants impaired IP3 signaling. Four mutations in the MRAP2 C-terminus affected internalization. MRAP2 variants had no effect on total or cell surface expression of either the MRAP2 or MC4R proteins. Structural models predicted that MRAP2 interacts with MC4R transmembrane helices 5 and 6, and mutations in two MRAP2 residues in putative contact sites impaired the ability of MRAP2 to facilitate MC4R signaling. In summary, our studies demonstrate that human MRAP2 variants associated with obesity impair multiple MC4R signaling pathways and that both Gs-cAMP and Gq-IP3 pathways should be assessed to determine variant pathogenicity.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978304","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}

{"title":"Insights into the molecular underpinning of type 2 diabetes complications.","authors":"Archit Singh, Ozvan Bocher, Eleftheria Zeggini","doi":"10.1093/hmg/ddae203","DOIUrl":"https://doi.org/10.1093/hmg/ddae203","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) complications pose a significant global health challenge. Omics technologies have been employed to investigate these complications and identify the biological pathways involved. In this review, we focus on four major T2D complications: diabetic kidney disease, diabetic retinopathy, diabetic neuropathy, and cardiovascular complications. We discuss advancements in omics research, summarizing findings from genetic, epigenomic, transcriptomic, proteomic, and metabolomic studies across different ancestries and disease-relevant tissues. We stress the importance of integrating multi-omics techniques to elucidate the biological mechanisms underlying T2D complications and advocate for ancestrally diverse studies. Ultimately, these insights will improve risk prediction for T2D complications and inform translation strategies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978303","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}

{"title":"Integration of multiomic data identifies core-module of inherited-retinal diseases.","authors":"Ajeet Singh, Rinki Ratnapriya","doi":"10.1093/hmg/ddaf001","DOIUrl":"https://doi.org/10.1093/hmg/ddaf001","url":null,"abstract":"<p><p>Human diseases with similar phenotypes can be interconnected through shared biological pathways, genes, or molecular mechanisms. Inherited retinal diseases (IRDs) cause photoreceptor dysfunction due to mutations in approximately 300 genes, affecting visual transduction, photoreceptor morphogenesis, and transcription factors, suggesting common pathobiological mechanisms. This study examined the functional relationship between known IRDs genes by integrating binding sites and gene expression data from the key photoreceptor transcription factors (TFs), Crx and Nrl. We show that the targets of these TFs were enriched in IRDs causal genes. Co-expression network analysis revealed that IRD-centric networks were disrupted when Crx and Nrl were knocked out. Finally, we identified a highly connected core module comprising 14 IRD and 39 target genes, of which 29 were dysregulated in the rod photoreceptors of the four IRD mouse models. These findings offer a network-based interpretation of IRDs, aiding in the identification of common mechanisms, prioritizing genes for novel disease gene identification, and informing the development of gene-agnostic therapies for IRDs.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964619","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}

{"title":"Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility.","authors":"Tihana Marić, Helen Castillo-Madeen, Monika Logara Klarić, Antun Barišić, Lovro Trgovec-Greif, Mark W Murphy, Anna-Grete Juchnewitsch, Kristiina Lillepea, Avirup Dutta, Lucija Žunić, Alexandra M Stendahl, Margus Punab, Kristjan Pomm, Daniel M Mendoza, Alexandra M Lopes, Ana Merkler Šorgić, Oliver Vugrek, Joao Gonçalves, Kristian Almstrup, Kenneth I Aston, Robert Belužić, Davor Ježek, Branimir Bertoša, Maris Laan, Ana Katušić Bojanac, Donald F Conrad, Maja Barbalić","doi":"10.1093/hmg/ddae197","DOIUrl":"https://doi.org/10.1093/hmg/ddae197","url":null,"abstract":"<p><p>The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher's exact test, p = 1.44 x 10-5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948180","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}

{"title":"Transcriptomic analysis of human cartilage identified potential therapeutic targets for hip osteoarthritis.","authors":"Jingyi Huang, Ming Liu, Andrew Furey, Proton Rahman, Guangju Zhai","doi":"10.1093/hmg/ddae200","DOIUrl":"https://doi.org/10.1093/hmg/ddae200","url":null,"abstract":"<p><p>Cartilage degradation is the hallmark of osteoarthritis (OA). The purpose of this study was to identify and validate differentially expressed genes (DEGs) in human articular cartilage that could serve as potential therapeutic targets for hip OA. We performed transcriptomic profiling in a discovery cohort (12 OA-free and 72 hip OA-affected cartilage) and identified 179 DEGs between OA-free and OA-affected cartilage after correcting for multiple testing (P < 2.97 × 10-6). Pathway and network analyses found eight hub genes to be associated with hip OA (ASPN, COL1A2, MXRA5, P3H1, PCOLCE, SDC1, SPARC, and TLR2), which were all confirmed using qPCR in a validation cohort (36 OA-free and 62 hip OA-affected cartilage) (P < 6.25 × 10-3). Our data showed that dysregulation of extracellular matrix formation and imbalance in the proportion of collagen chains may contribute to the development of hip OA, and SDC1 could be a promising potential therapeutic target. These findings provided a better understanding of the molecular mechanisms for hip OA and may assist in developing targeted treatment strategies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948183","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}

{"title":"Q241R mutation of Braf causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome, independent of developmental malformations.","authors":"Akira Moriya, Shin-Ichi Inoue, Fumihito Saitow, Moe Keitoku, Noato Suzuki, Etsumi Oike, Eriko Urano, Eiko Matsumoto, Hidenori Suzuki, Yoko Aoki, Hiroshi Ohnishi","doi":"10.1093/hmg/ddae196","DOIUrl":"https://doi.org/10.1093/hmg/ddae196","url":null,"abstract":"<p><p>Constitutively active mutants of BRAF cause cardio-facio-cutaneous (CFC) syndrome, characterized by growth and developmental defects, cardiac malformations, facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, the systemic BrafQ241R/+ mutant mouse, has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutations on neural function, separately from their effects on developmental processes. To this end, we generated Braf mutant mice expressing BRAFQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development. Behavioral analysis revealed that n-BrafQ241R/+ mice exhibited reduced home cage activity and learning disability, which were similar to those of systemic BrafQ241R/+ mice. The active form of ERK was increased in the hippocampus of n-BrafQ241R/+ mice, whereas basal synaptic transmission and synaptic plasticity in hippocampal Schaffer collateral-CA1 synapses seems to be normal. Transcriptome analysis of the hippocampal tissue revealed significant changes in the expression of genes involved in regulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway, synaptic function and memory formation. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of the RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain. A similar mechanism may be possible in human CFC syndrome.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948181","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}

{"title":"The evaluation of targeted exome sequencing of candidate genes in a Han Chinese population with primary open-angle glaucoma.","authors":"Yiwen Zhou, Youjia Zhang, Qingdan Xu, Xinghuai Sun, Yuhong Chen","doi":"10.1093/hmg/ddae198","DOIUrl":"https://doi.org/10.1093/hmg/ddae198","url":null,"abstract":"<p><p>Primary open-angle glaucoma (POAG), known as a common ocular disease with genetic heterogeneity, is characterized by progressive optic disc atrophy and visual field defects. This study aimed to assess the contribution of previously reported POAG-associated genes and investigate potential functional variations and genotype-phenotype correlations in a Han Chinese population. DNA from 500 cases and 500 controls was pooled and sequenced using a customized panel of 398 candidate genes. After prioritization, 21 SNPs from 16 genes were genotyped in the first replication cohort (500 cases and 500 controls), and 9 SNPs were genotyped in the second replication cohort (500 cases and 500 controls). Allelic associations and odds ratios were adjusted for age and sex, while linear regression assessed SNP correlations with POAG endophenotypes. Haplotype analysis and linkage disequilibrium were performed using Haploview. In silico prediction tools were used to predict pathogenicity and function. SNPs from MFN2, DGKG, PKHD1, PTPRJ, and LTBP2 were associated with POAG in at least one cohort, and SNPs from EXOC2, PTPRJ, and LTBP2 showed significant correlations with intraocular pressure. Additionally, haplotype analysis revealed a significant association between the EXOC2 TGC haplotype and POAG risk. We validated several candidate genes and identified novel SNPs, providing further insight into the genetic architecture of POAG in the Han Chinese population.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948182","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}