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":"Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation.","authors":"Michelle L Brinkmeier, Leonard Y M Cheung, Sean P O'Connell, Diana K Gutierrez, Eve C Rhoads, Sally A Camper, Shannon W Davis","doi":"10.1093/hmg/ddaf032","DOIUrl":"10.1093/hmg/ddaf032","url":null,"abstract":"<p><p>Nucleoredoxin (Nxn) encodes a multi-functional enzyme with oxidoreductase activity that regulates many different signaling pathways and cellular processes in a redox-dependent manner. Rare NXN mutations are reported in individuals with recessive Robinow syndrome, which involves mesomelic skeletal dysplasia, short stature, craniofacial dysmorphisms, and incompletely penetrant heart and palate defects. Here we report that Nxn is expressed in the ventral diencephalon and developing pituitary gland, and that Nxn deficient mice have pituitary dysmorphology and craniofacial abnormalities that include defects in the skull base and cleft palate. Nxn mutant mice exhibit reduced WNT signaling and reduced differentiation of pituitary stem cells into hormone-producing cells. These results suggest patients with Robinow syndrome could benefit from evaluation by endocrinologists for pituitary structural imaging and hormone insufficiency.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566926","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":"Mate-pair sequencing assisted prenatal counseling for a rare complex chromosomal rearrangement carrier.","authors":"Lu Wan, Zeng Baitao, Tan Yuxin, Chen Zhongfa, Zhou Jihui, Huang Ning, Yang Bicheng, Huang Shuhui, Liu Yanqiu, Yuan Huizhen","doi":"10.1093/hmg/ddaf012","DOIUrl":"https://doi.org/10.1093/hmg/ddaf012","url":null,"abstract":"<p><strong>Objective: </strong>This study was aimed to identify a rare complex rearrangement and assist prenatal counseling.</p><p><strong>Method: </strong>Mate-pair sequencing (MPseq) combined with karyotypes, copy number variants sequencing and whole exome sequencing was used to provide accurate chromosome breakpoints and assist prenatal diagnosis for a mentally retarded pregnant woman.</p><p><strong>Result: </strong>MPseq indicated a complex rearrangement involved 25 breakpoints and fusions, disrupting 6 genes. Among which, ZMIZ1 was associated with neurodevelopmental disorders with dysmorphic facies and distal skeletal abnormalities, which was consistent with the phenotype of pregnant women.</p><p><strong>Conclusion: </strong>MPseq was a cost-effective and accurate method that could be used as a complementary tool for human genetic diagnosis and prenatal counseling.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566924","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":"A novel recurrent ARL3 variant c.209G > A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models.","authors":"Julio C Corral-Serrano, Veronika Vaclavik, Stijn Van de Sompele, Karolina Kaminska, Katarina Jovanovic, Pascal Escher, Filip Van den Broeck, Francesca Cancellieri, Vasileios Toulis, Bart P Leroy, Julie de Zaeytijd, Zhixuan You, Daniele Ottaviani, Mathieu Quinodoz, Gabriela Bordeanu, Alison J Hardcastle, Frauke Coppieters, Viet H Tran, Michael E Cheetham, Carlo Rivolta, Elfride De Baere","doi":"10.1093/hmg/ddaf029","DOIUrl":"https://doi.org/10.1093/hmg/ddaf029","url":null,"abstract":"<p><p>Inherited retinal dystrophies (IRDs) are characterized by their high clinical and genetic heterogeneity. Despite significant advances in the identification of genes associated with IRDs, many individuals and families still have not received a definite molecular diagnosis. Here, we performed clinical examinations and conducted genetic testing in five families with IRD. Whole exome sequencing in the five index cases revealed a heterozygous missense variant, c.209G > A, p.(Gly70Glu) in the ARL3 gene (NM_004311.4). A de novo occurrence was demonstrated in one affected individual and autosomal dominant inheritance in nine affected individuals from four families. Their phenotypes displayed variable expressivity, and ranged from rod-cone to cone-rod dystrophy with photophobia. Human induced pluripotent stem cells (hiPSCs) were generated from dermal fibroblasts from the individual with the de novo ARL3 variant and were differentiated to retinal pigment epithelium cells (RPE) and retinal organoids. Immunofluorescence analyses in these models showed decreased INPP5E localization within the cilia of RPE and connecting cilia of retinal organoids, as well as reduced PDE6⍺ in the organoid outer segments, suggesting that the p.(Gly70Glu) variant causes IRD by defective lipidated protein transport in photoreceptors and/or RPE. This is the first study of ARL3 dysfunction in human retinal cells, highlighting its importance for retinal homeostasis, as well as a variability in the clinical presentation of ARL3-associated IRD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556607","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":"Correction to: Expression variation of long noncoding RNAs in dopaminergic cells-derived from stem cells and their MPP+ induced PD models.","authors":"","doi":"10.1093/hmg/ddaf034","DOIUrl":"10.1093/hmg/ddaf034","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556706","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":"New selective androgen receptor modulator TEI-SARM2 improves muscle function in a Duchenne muscular dystrophy rat model.","authors":"Katsuyuki Nakamura, Masanobu Kanou, Wataru Fujii, Karina Kouzaki, Toshie Jimbo, Keitaro Yamanouchi, Koichi Nakazato, Hiroshi Ueda, Jun Hirata, Kei Yamana","doi":"10.1093/hmg/ddaf028","DOIUrl":"https://doi.org/10.1093/hmg/ddaf028","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by a genetic mutation in the Dmd gene. Dystrophin mutant mice (mdx) have traditionally been used for DMD research as a disease model in the preclinical stage; however, mdx mice exhibit only very mild phenotypes to partially mimic muscle degeneration and regeneration. To overcome this limitation in preclinical studies, DMD mutant rats (DMD rats) generated by CRISPR/Cas were used as a DMD model to exhibit age-dependent progressive muscle degeneration and pathophysiological features similar to DMD patients and more severe than those displayed by mdx mice. TEI-SARM2 is a non-steroidal, orally available selective androgen receptor modulator (SARM) developed as a pharmaceutical candidate for the treatment of muscle wasting diseases based on its potent anabolic activity on skeletal muscle mass. In this study, long-term treatment of daily oral administration of TEI-SARM2 to DMD rats significantly improved muscle function (endurance and strength) assessed by grip and tetanic force measurements. TEI-SARM2 did not increase the muscle weight of hindlimbs in male DMD rats; moreover, long-term, weekly oral administration for 24 weeks improved muscle function with reduced side effects on the prostate and testes weight. Histological analysis showed that TEI-SARM2 significantly reduced adipose tissue infiltration in DMD muscle. In female DMD rats, both daily and weekly TEI-SARM2 treatment showed anabolic effects and enhanced muscle strength and endurance. Taken together, these results indicate that TEI-SARM2 has non-anabolic and anabolic effects that improve dystrophic muscle dysfunction and can be a supportive therapeutic option for DMD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556707","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}