Human molecular genetics最新文献

{"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":"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":"481-491"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891871/pdf/","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":"OA","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":"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":"492-511"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","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":"Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.","authors":"Nithya N Nair, Rachel A Kline, Imogen Boyd, Meenakshi Anikumar, Adrian Thomson, Douglas J Lamont, Gillian A Gray, Thomas M Wishart, Lyndsay M Murray","doi":"10.1093/hmg/ddaf006","DOIUrl":"10.1093/hmg/ddaf006","url":null,"abstract":"<p><p>Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"547-562"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","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":"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":"533-546"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891872/pdf/","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":"OA","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":"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":"469-480"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891870/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A TAF11 variant contributes to non-syndromic cleft lip only through modulating neural crest cell migration.","authors":"Dandan Li, Yu Tian, Barbara Vona, Xin Yu, Junyan Lin, Lan Ma, Shu Lou, Xiaofeng Li, Guirong Zhu, Yuting Wang, Mulong Du, Lin Wang, Yongchu Pan","doi":"10.1093/hmg/ddae188","DOIUrl":"10.1093/hmg/ddae188","url":null,"abstract":"<p><p>The NC_000006.12: g.34887814C>G variant in TAF11 was identified as a potential functional variant in a Chinese pedigree including two non-syndromic cleft lip only (NSCLO) cases. Applying Chromatin Immunoprecipitation (ChIP), Electrophoretic mobility shift and super-shift assays, we found that the mutant G allele recruited more STAT1 and STAT3, and increased the expression of TAF11. RNA sequencing, GO and KEGG pathway enrichment, ChIP and dual-luciferase reporter assays revealed that TAF11 downregulated CDH1 and CTNND1 in the cell adhesion pathway by binding to their promoter regions and inhibiting transcriptional activities. Alcian blue staining, time-lapse photography, whole-mount in situ hybridization, phospho-Histone H3 immunofluorescence and TUNEL assays indicated that TAF11 and taf11 overexpression (TAF11OE and taf11OE, respectively) contributed to disturbed migration of cranial neural crest cells and abnormal craniofacial development, as well as increased death and deformity rates in zebrafish. In conclusion, a functionally relevant TAF11 variant, affecting cell migration via modulating CDH1 and CTNND1, was associated with etiology of NSCLO.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"392-401"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894074","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":"Retraction of: Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.","authors":"","doi":"10.1093/hmg/ddae149","DOIUrl":"10.1093/hmg/ddae149","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"467"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease.","authors":"Yudi Xu, Shutong Liu, Zhaokai Zhou, Hongzhuo Qin, Yuyuan Zhang, Ge Zhang, Hongxuan Ma, Xinwei Han, Huimin Liu, Zaoqu Liu","doi":"10.1093/hmg/ddae189","DOIUrl":"10.1093/hmg/ddae189","url":null,"abstract":"<p><p>Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"381-391"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846508","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":"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":"454-465"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","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":"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":"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":"444-453"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834983/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}