Frontiers in Genetics最新文献

{"title":"Genomic-based genetic parameters and genome-wide association studies for productive and reproductive traits in Beef-on-Dairy crossbreds.","authors":"R H Ahmed, C Schmidtmann, J Mugambe, G Thaller","doi":"10.3389/fgene.2025.1530310","DOIUrl":"10.3389/fgene.2025.1530310","url":null,"abstract":"<p><strong>Background: </strong>Beef on Dairy (BoD) calves are born from the crossing of dairy cows with beef breeds. The genetic architecture of these calves differs significantly from the parent breeds due to heterosis and other dominance effects. Identification of the genomic regions associated with traits in BoD calves and the inheritance pattern of these regions can assist in the selection process. We conducted a genome-wide association study (GWAS) for Belgian blue and Angus crossbreds born from a Holstein dam, incorporating additive and dominance effects to identify genomic regions associated with birth weight, calving difficulty, and gestation length. Additionally, a haplotype-based GWAS was performed to compare the effectiveness of these two different methodologies and to identify the parental origin of the haplotypes based on similar allelic patterns between crossbred and parental breeds.</p><p><strong>Results: </strong>The heritability estimates for birth weight, calving difficulty, and gestation length were 0.29 (±0.03), 0.36 (±0.04), and 0.09 (±0.03), respectively. Using SNP-based GWAS for birth weight, a genomic region containing the <i>GABRG1</i> gene on BTA 6 was identified. In addition, the haplotype-based analysis identified three more genes (<i>CSER1</i>, <i>FAM13A</i>, and <i>LCORL</i>) associated with birth weight. Incorporating dominance effects into the GWAS model led to the identification of an additional gene, <i>SPP1</i>, related to birth weight. For calving difficulty, SNP-based GWAS in Angus crossbreds revealed a genomic region containing the <i>KCNIP4</i> gene. Most of the haplotypes associated with these traits originated from the three parental breeds, but six unique haplotypes for Angus and Belgian blue were identified.</p><p><strong>Conclusion: </strong>Based on this study, Haplotype GWAS was found to have superior statistical power in the identification of associated genomic regions in BoD crossbreds. However, for traits such as calving difficulty, SNP-based GWAS proved to be more effective. Both approaches are essential for the identification of genomic regions associated with traits of interest in BoD calves.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1530310"},"PeriodicalIF":2.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"K-rice: a comprehensive database of Korean rice germplasm variants.","authors":"Jeong-Gu Kim, Gyu-Hwang Park, Jinhyun Kim, Jinho Jeong, Tae-Ho Lee","doi":"10.3389/fgene.2025.1544652","DOIUrl":"10.3389/fgene.2025.1544652","url":null,"abstract":"","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1544652"},"PeriodicalIF":2.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Proficiency testing in histocompatibility and immunogenetics: current status and future perspectives.","authors":"Martin Petrek, Kelley M K Hitchman","doi":"10.3389/fgene.2025.1619032","DOIUrl":"https://doi.org/10.3389/fgene.2025.1619032","url":null,"abstract":"","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1619032"},"PeriodicalIF":2.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polymorphisms in circadian rhythm genes and the risk of differentiated thyroid cancer.","authors":"Takiy-Eddine Berrandou, Emilie Cordina-Duverger, Claire Mulot, Anne-Valérie Guizard, Claire Schvartz, Pierre Laurent-Puig, Monia Zidane, Florent De Vathaire, Pascal Guénel, Thérèse Truong","doi":"10.3389/fgene.2025.1539090","DOIUrl":"10.3389/fgene.2025.1539090","url":null,"abstract":"<p><strong>Introduction: </strong>Circadian rhythms are controlled by biological clocks regulated at the molecular level by a set of circadian genes operating through a negative feedback loop. These genes also regulate key biological processes, including cell proliferation, cell cycle, and apoptosis.</p><p><strong>Methods: </strong>We investigated the role of circadian gene polymorphisms in the risk of differentiated thyroid cancer (DTC) and their interaction with DTC risk factors. Data were obtained from 463 DTC cases and 482 unrelated controls of European ancestry, selected from two population-based case-control studies conducted in France. Associations with 570 single nucleotide polymorphisms (SNPs) in 23 circadian genes were evaluated using multivariate logistic regression models. Gene- and pathway-level associations and gene-environment interactions were analyzed using the adaptive rank truncated product (ARTP) method.</p><p><strong>Results and discussion: </strong>We found no significant association between DTC risk and circadian gene polymorphisms at the SNP, gene, or pathway levels. However, we observed statistically significant interactions between smoking status and SNPs rs11204897 (<i>RORC</i>) and rs1012477 (<i>PER3</i>), as well as with the <i>PER3</i> gene and the overall circadian pathway. These results suggest that smoking status may modulate the association between DTC and polymorphisms in circadian genes. Further studies are needed to confirm these findings.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1539090"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene expression profiles identify key factors in inflammatory odontoblastic dental pulp stem cell differentiation via TNFα/C5L2.","authors":"Muhammad Irfan, Ji Hyun Kim, Sreelekshmi Sreekumar, Seung Chung","doi":"10.3389/fgene.2025.1592599","DOIUrl":"10.3389/fgene.2025.1592599","url":null,"abstract":"<p><strong>Introduction: </strong>Inflammation is a complex host response to harmful infections or injuries, playing beneficial and detrimental roles in tissue regeneration. Notably, clinical dentinogenesis associated with caries development occurs within an inflammatory environment. Reparative dentinogenesis is closely linked to intense inflammation, which triggers the recruitment and differentiation of dental pulp stem cells (DPSCs) into the dentin lineage. Understanding how inflammatory responses influence DPSCs is essential for elucidating the mechanisms underlying dentin and pulp regeneration.</p><p><strong>Methods: </strong>Given the limited data on this process, a broad approach is employed here to understand better the complex mechanisms involved and identify downstream signaling targets. This study investigates the role of inflammation and the complement receptor C5L2 in the odontoblastic differentiation of DPSCs and the associated transcriptomic changes using poly-A RNA sequencing (RNA-seq). RNA-seq techniques provide insight into the transcriptome of a cell, offering higher coverage and greater resolution of its dynamic nature.</p><p><strong>Results: </strong>Following inflammatory stimulation, DPSCs exhibit significantly altered gene profiles, including marked up-regulation of key odontogenic genes, highlighting the critical role of inflammation in dentinogenesis. We demonstrate that TNFα-treated, odontoblast-like differentiating DPSCs, under C5L2 modulation, show differentially expressed gene profiles and transcriptomic changes.</p><p><strong>Conclusion: </strong>Beyond quantifying gene expression, RNA-seq data also enable the discovery of novel transcripts, the identification of alternatively spliced genes, and the detection of allele-specific expression. The data presented may offer new avenues for experimental approaches to uncovering pathways in dentinogenesis by identifying specific transcription factors and gene profiles.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1592599"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Religious factors predict support for genomic medicine more strongly than politics, education, or trust: A survey of 4,939 adults in the United States.","authors":"James M DuBois, Eu Gene Chin, Erin D Solomon, Jenine K Harris, Peter Hill, Kari Baldwin, Lauren L Baker","doi":"10.3389/fgene.2025.1587774","DOIUrl":"10.3389/fgene.2025.1587774","url":null,"abstract":"<p><strong>Background: </strong>Religious affiliation and attendance at services is associated with lower levels of support for some genomic activities, such as genetic testing. However, little is known about why or how religion shapes attitudes toward genomics.</p><p><strong>Materials and methods: </strong>We conducted a cross-sectional survey with 4,939 participants representative of nine religious groups in the US (including atheist and agnostic). The survey examined (a) attitudes toward diverse activities associated with genomic medicine, (b) religious beliefs and practices, (c) control variables including trust in the healthcare system and knowledge of genetics, and (d) demographics. We examined differences between groups using an Analysis of Covariance (ANCOVA), and developed a regression model to identify significant predictors of support for genetic medicine.</p><p><strong>Results: </strong>When controlling for demographic variables, only small attitudinal differences existed between religious groups, though substantial variability existed within groups. Only seven variables uniquely predicted attitudes toward genomic medicine: acceptance of evolution, support for promoting community health within their spiritual community, knowledge of genetics, more permissive attitudes toward reproduction and end of life care within their spiritual community, distrust in the healthcare system, political orientation, and frequency of volunteering (in descending order).</p><p><strong>Discussion: </strong>Our findings suggest that stereotyping based on religious affiliation is seriously misguided, and engagement with religious groups on genomic medicine must go beyond education and address moral issues and worldviews.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1587774"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging perspectives on osteonecrosis of the femoral head: the role of circular RNAs and long non-coding RNAs - a systematic review.","authors":"Feifei Lin, Shicheng Zhou, Min Yi, Qingyu Wang","doi":"10.3389/fgene.2025.1549684","DOIUrl":"10.3389/fgene.2025.1549684","url":null,"abstract":"<p><strong>Background: </strong>Osteonecrosis of the femoral head (ONFH) is a prevalent and challenging orthopedic condition that often leads to hip pain and dysfunction. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as potent regulators of gene expression that influence both transcriptional and post-transcriptional processes in ONFH pathogenesis. This study aimed to investigate the association between dysregulated lncRNAs and circRNAs and their functions in ONFH.</p><p><strong>Methods: </strong>We performed a systematic literature review of PubMed, MEDLINE, and Web of Science for all publicly available data. We included papers published before 17 April 2024, to evaluate the regulatory role and differential expression of lncRNAs and circRNAs in ONFH.</p><p><strong>Results: </strong>Forty-four eligible studies were retrieved from PubMed, MEDLINE, and Web of Science, including 19 expression profiling studies, 19 gene studies, and six therapeutic studies. A total of 37 circRNAs and 42 lncRNAs were identified using quantitative real-time PCR (qRT-PCR). Dynamic changes in lncRNA and circRNA expression are associated with the proliferation and apoptosis of bone marrow stem cells (BMSCs), bone marrow endothelial cells (BMECs), and necrotic bone tissues in ONFH. CircHIPK3 and circHGF act as miRNA sponges to disrupt the osteogenic-adipogenic equilibrium, whereas lncRNA SNHG1 and GAS5 directly suppress osteogenesis. Notably, HOX transcript antisense intergenic RNA (HOTAIR), LncAABR07053481, Miat, and LINC00473 play significant roles in ameliorating the abnormal differentiation of BMSCs and could be promising therapeutic targets for ONFH.</p><p><strong>Conclusion: </strong>This systematic review discusses the current understanding of the involvement of lncRNAs and circRNAs in ONFH pathogenesis. Despite these promising findings, the limitations include heterogeneity in the study design and insufficient <i>in vivo</i> validation. This work consolidates ncRNA-mediated pathways in ONFH, offering novel targets for early diagnosis and RNA-based therapies, while advocating standardized multi-omics approaches in future research.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1549684"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MOLUNGN: a multi-omics graph neural network for biomarker discovery and accurate lung cancer classification.","authors":"Daifeng Zhang, Guoqiang Bian, Yuanbin Zhang, Jiadong Xie, Chenjun Hu","doi":"10.3389/fgene.2025.1610284","DOIUrl":"10.3389/fgene.2025.1610284","url":null,"abstract":"<p><strong>Introduction: </strong>Lung cancer continues to pose significant global health burdens due to its high morbidity and mortality. This study aimed to systematically integrate biomedical datasets, particularly incorporating traditional Chinese medicine (TCM)-associated multi-omics data, employing advanced deep-learning methods enhanced by graph attention mechanisms. We sought to investigate molecular mechanisms underlying stage-wise lung cancer progression and identify pivotal stage-specific biomarkers to support precise cancer staging classification.</p><p><strong>Methods: </strong>We developed a novel multi-omics integrative model, named the Multi-Omics Lung Cancer Graph Network (MOLUNGN), based on Graph Attention Networks (GAT). Clinical datasets of non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), were analyzed to create omics-specific feature matrices comprising mRNA expression, miRNA mutation profiles, and DNA methylation data. MOLUNGN incorporated omics-specific GAT modules (OSGAT) combined with a Multi-Omics View Correlation Discovery Network (MOVCDN), effectively capturing intra- and inter-omics correlations. This framework enabled comprehensive classification of clinical cases into precise cancer stages, alongside the extraction of stage-specific biomarkers.</p><p><strong>Results: </strong>Evaluations utilizing publicly available datasets confirmed MOLUNGN's superior performance over existing methodologies. On the LUAD dataset, MOLUNGN achieved accuracy (ACC) of 0.84, Recall_weighted of 0.84, F1_weighted of 0.83, and F1_macro of 0.82. On the LUSC dataset, the model further improved, achieving ACC of 0.86, Recall_weighted of 0.86, F1_weighted of 0.85, and F1_macro of 0.84. Notably, critical stage-specific biomarkers with significant biological relevance to lung cancer progression were identified, facilitating robust gene-disease associations.</p><p><strong>Discussion: </strong>Our findings underscore the efficacy of MOLUNGN as an integrative framework in accurately classifying lung cancer stages and uncovering essential biomarkers. These biomarkers provide deep insights into lung cancer progression mechanisms and represent promising targets for future clinical validation. Integrating these biomarkers into the TCM-target-disease network enriches the understanding of TCM therapeutic potentials, laying a robust foundation for future precision medicine applications.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1610284"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>NOS3</i> rs3918188C>A is associated with susceptibility to resistant hypertension while <i>CES1</i> genetic variation was not associated with resistant hypertension among South Africans.","authors":"Jonathan N Katsukunya, Revina Naicker, Nyarai D Soko, Dirk Blom, Phumla Sinxadi, Emile R Chimusa, Brian Rayner, Erika Jones, Collet Dandara","doi":"10.3389/fgene.2025.1608423","DOIUrl":"10.3389/fgene.2025.1608423","url":null,"abstract":"<p><strong>Introduction: </strong>Genetic variation in genes coding for enzymes metabolising antihypertensive drugs, may affect the efficacy of angiotensin converting enzyme (ACE) inhibitors such as enalapril, potentially leading to resistant hypertension (RHTN). We set out to evaluate the contribution of genetic variation in <i>CES1</i> and <i>NOS3</i> genes on susceptibility to RHTN, as well as estimate the frequencies of <i>CES1</i> copy number variation (CNV) in African and Mixed Ancestry (MA) populations of South Africa.</p><p><strong>Methods: </strong>Using a retrospective age, sex and ethnicity matched case-control study design, 379 participants with hypertension belonging to the African and MA ethnic groups were recruited. Cases were participants with RHTN (i.e., blood pressure (BP) ≥140/90 mmHg on ≥3 antihypertensive drugs or BP < 140/90 mmHg on >3 antihypertensive drugs, including a diuretic). Cases were matched to controls with similar characteristics (age (±5 years), sex and ethnicity) in a 1:1 ratio. Controls were participants with hypertension that was under control (BP < 140/90 mmHg on ≤3 antihypertensive drugs). Five polymorphisms in <i>CES1</i> and <i>NOS3</i> were characterized using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), quantitative PCR and validated using Sanger sequencing. The additive model of inheritance and multivariable logistic regression were used to determine associations between genotypes and RHTN while adjusting for potential confounding variables.</p><p><strong>Results and discussion: </strong><i>NOS3</i> rs3918188A/A (aOR: 0.13; CI: 0.04-0.41; P = 0.0009) genotype and <i>NOS3</i> rs2070744-rs1798883-rs3918188G-T-A haplotype (OR: 0.54; CI: 0.37-0.78; P = 0.001) appeared to confer protection against RHTN among MA participants only. <i>CES1</i> rs2244613C>A and <i>CES1</i> CNV were not significantly associated with RHTN. However, there appeared to be quantitative differences in <i>CES1</i> CNV profiles across ethnic groups. We speculate that <i>NOS3</i> rs3918188A allele may affect <i>NOS3</i> gene expression, potentially leading to increased amounts of the vasodilator, nitric oxide (NO) and favourable outcomes in individuals taking antihypertensives drugs such as enalapril.</p><p><strong>Conclusion: </strong><i>NOS3</i> genetic variation seems important in the susceptibility to RHTN among Africans and requires further studies.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1608423"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-phenotype analysis and functional study of three novel <i>LRP6</i> variants in non-syndromic oligodontia.","authors":"Yunyun Yuan, Ya Zhao, Lingqiang Meng, Shuyun Zheng, Hui Li, Jiabao Ren, Beibei Li, Chenyun Dou, Yan Hou, Wenjing Chen, Jing Zhang, Yulin Ding, Wenjing Shen","doi":"10.3389/fgene.2025.1598907","DOIUrl":"10.3389/fgene.2025.1598907","url":null,"abstract":"<p><strong>Introduction: </strong>Tooth agenesis (TA) is a common craniofacial malformation in humans, characterized by the absence of one or more permanent teeth. Recent studies have identified the low-density lipoprotein receptor-related protein 6 (<i>LRP6</i>) gene as an autosomal dominant contributor to TA. Herein we aimed to identify novel <i>LRP6</i> variants in patients with non-syndromic oligodontia (NSO) and perform functional analyses of these variants.</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was conducted on probands and their first-degree relatives to identify potential pathogenic variants. Identified LRP6 variants underwent computational pathogenicity prediction using integrated bioinformatics tools. Subcellular localization patterns were analyzed via immunofluorescence microscopy. Functional characterization of WNT/β-catenin signaling alterations was achieved through Western blot analysis and dual-luciferase reporter assays (TOP-Flash/FOP-Flash systems). Finally, genotype-phenotype correlations in <i>LRP6</i>-associated non-syndromic oligodontia (NSO) were systematically investigated.</p><p><strong>Results: </strong>We identified three novel <i>LRP6</i> variations (NM_002336): a truncating variant [c.2182C>T (p.Arg728*)] and two missense variants [c.3773C>T (p.Thr1258Met) and c.1441C>T (p.Arg481Cys)]. Immunofluorescence characterization revealed that the missense variants exhibited subcellular localization patterns comparable to wild-type LRP6, with predominant distribution in the plasma membrane and cytoplasmic compartments. Western blot analysis revealed impaired β-catenin expression in cells harboring the <i>LRP6</i> missense variants, suggesting compromised canonical WNT signaling pathway activity. Functional assessment using the TOP/FOP-Flash luciferase reporter system demonstrated significantly reduced <i>TCF/LEF</i> transcriptional activity associated with these variants, though statistical significance was exclusively observed for the Arg481Cys variant (<i>P</i> < 0.05). Literature review identified 39 <i>LRP6</i> variants associated with 52 NSO patients, revealing that mandibular second premolars were the most frequently affected teeth, while maxillary first molars were least likely to be affected.</p><p><strong>Discussion: </strong>We identified three novel <i>LRP6</i> variants in patients with NSO from three Chinese families. Furthermore, we have confirmed through <i>in vitro</i> experiments that these novel <i>LRP6</i> missense variants lead to impaired activation of the WNT signalling pathway. Finally, we summarized the genotype-phenotype correlation for <i>LRP6</i>-related NSO, finding that <i>LRP6</i> variants are most likely to affect the mandibular second premolars.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1598907"},"PeriodicalIF":2.8,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}