Human Mutation最新文献

{"title":"TCIRG1 as a Novel Prognostic Biomarker Triggering Immune Infiltration in Renal Clear Cell Carcinoma: An Integrative Study of Single-Cell and Bulk Data","authors":"Wei Ye, Honghao Yang, Xincheng Yi, Shaoyi Zhang, Siyu Wang, Zongming Jia, Jin Zang","doi":"10.1155/humu/1839494","DOIUrl":"https://doi.org/10.1155/humu/1839494","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Tumor microenvironment (TME) is a significant factor regulating the malignant phenotype and drug resistance of kidney renal clear cell carcinoma (KIRC). The identification of biomarker signatures mediating immune infiltration in TME is of significance for prognostic assessment and personalized therapy of KIRC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The gene set associated with immune cell populations in KIRC TME was extracted from the single-cell dataset GSE139555 using high-dimensional weighted coexpression network analysis (hdWGCNA). The bulk data from TCGA-KIRC were integrated to screen significant signatures in KIRC prognosis through Cox regression, and a combination of 101 machine learning algorithms was compared to prioritize feature genes for the construction of a novel prognostic model. Finally, LightGBM and XGBoost algorithms identified TCIRG1 as a key model feature and a novel biomarker in KIRC for experimental characterization using western blot, immunohistochemistry, multiple immunofluorescence (mIHC), subcutaneous tumor formation in nude mice, and Transwell assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Single-cell data showed that the monocyte population varied most significantly in KIRC samples, and 150 candidate genes from monocytes were identified based on hdWGCNA. By integrating bulk TCGA-KIRC data and Cox regression, 15 prognosis-related genes were extracted as candidates for machine learning–powered training using 101 algorithm combinations, and nine genes were prioritized as feature variables to establish a prognostic model with good predictive performance on the overall survival of KIRC patients. Finally, TCIRG1 was identified as a novel biomarker signature from the prognostic model, and ultimately, by combining LightGBM and XGBoost algorithms, TCIRG1 was identified as a key characteristic signal for experimental validation and functional studies. Immunohistochemistry, cellular, and animal experiments showed that TCIRG1 expression was significantly elevated in KIRC samples, and its high expression was closely associated with adverse clinicopathological features. mIHC results demonstrated a significant positive correlation between TCIRG1 expression and immune cell infiltration in the KIRC TME, particularly with Treg cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>TCIRG1 was identified and validated as a novel prognostic biomarker triggering immune infiltration in KIRC. The mechanisms and translational prospects of TCIRG1 in KIRC management will be explored in future work.</p>\u0000 ","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1839494","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145366942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced ICOS Signaling Between Dendritic Cells and T Cells Characterizes the Immune Landscape of Human Cholangiocarcinoma","authors":"Meiying Zhu,&nbsp;Yuou Li,&nbsp;Xiaolong Tang,&nbsp;Xinjian Wan,&nbsp;Zunqiang Zhou","doi":"10.1155/humu/9981470","DOIUrl":"https://doi.org/10.1155/humu/9981470","url":null,"abstract":"<p>Cholangiocarcinoma exhibits a complex tumor microenvironment, yet the cellular interactions governing its progression remain poorly understood. Here, through integrated analysis of two independent single-cell RNA sequencing datasets comprising both complete tissue and immune-focused profiling, we comprehensively mapped the cellular landscape and intercellular communication networks in human cholangiocarcinoma. Our analysis revealed significant remodeling of immune cell compositions and interaction patterns in the tumor microenvironment. Notably, we identified enhanced ICOS signaling between dendritic cells and T cells as a prominent feature of cholangiocarcinoma. Using CellChat analysis, we demonstrated that tumor-associated dendritic cells, particularly plasmacytoid DCs, exhibit stronger ICOS-mediated communication with T cells compared to their counterparts in normal tissues. Functional validation experiments confirmed that tumor-conditioned dendritic cells upregulate ICOSL expression and promote CD8+ T-cell activation through the ICOS–ICOSL axis, as evidenced by increased CD69 and CD25 expression. This activation was specifically abolished by ICOSL blockade, establishing the functional significance of this pathway. Our findings provide novel insights into tumor-immune interactions in cholangiocarcinoma and suggest the ICOS–ICOSL axis as a potential therapeutic target for immunotherapy.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9981470","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145366716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Novel Modifier Genes Associated With Pain in Cystic Fibrosis: An In Silico Gene Discovery","authors":"Anastasia Ward,&nbsp;Ramil Mauleon,&nbsp;Chee Y. Ooi,&nbsp;Nedeljka Rosic","doi":"10.1155/humu/7570437","DOIUrl":"https://doi.org/10.1155/humu/7570437","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cystic fibrosis (CF) is the most common life-shortening monogenic autosomal recessive disease in Caucasians with diverse and extensive comorbidities. Where the majority of studies have focused on the respiratory and digestive systems, there has been a paucity of research focusing on pain, even though people living with CF have reported a high prevalence and increased severity of pain. Many studies have identified the complex relationship between genotype and phenotype, and growing evidence suggests that the phenotypic variation observed not only depends on the variations in the CF transmembrane conductance regulator (<i>CFTR</i>) gene but also on modifier genes. Gene modifiers (GMs) have been reported to affect many organs or systems in CF. However, there have been no studies on how GMs may influence pain. Therefore, this study is aimed at highlighting potential modifier genes that may affect pain perception in CF and possible responses to therapeutics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The bioinformatics workflow adopted includes database and literature mining, pathway enrichment analysis, protein–protein interactions evaluation and drug–gene network investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified seven potential pain modifiers in CF, including chymotrypsin C (<i>CTRC</i>), serine protease inhibitor Kazal-Type 1 (<i>SPINK1</i>), tumour necrosis factor (<i>TNF</i>), ATP-binding cassette subfamily B Member 1 (<i>ABCB1</i>), protease serine 1 (<i>PRSS1</i>) and transforming growth factor beta 1 (<i>TGFB1</i>) interacting with the <i>CFTR</i> gene. The analysis of the biochemical pathways indicates that signal transduction and the immune system are likely to be involved in pain processes. The specific GMs, <i>TNF</i> and <i>ABCB1</i>, are found to be within the central hub genes, indicating their potential influence on the pain pathways in CF.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This in silico analysis highlights potential genes and biochemical pathways implicated in pain pathways that could significantly impact pain perception in people living with CF and their response to prescribed therapies. Further functional analyses are needed to include CF participants and provide a physiological relevance on how genetic polymorphisms of identified GMs may impact their pain phenotype or profile.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7570437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145317619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Immunotherapy Response and Prognostic Outcomes for Patients With Ovarian Cancer Using PANoptosis-Related Genes","authors":"Lei Zhang,&nbsp;Bo Yang,&nbsp;Huiting Xiao,&nbsp;Lu Sun,&nbsp;Wenting He,&nbsp;Ying Chen","doi":"10.1155/humu/7108361","DOIUrl":"https://doi.org/10.1155/humu/7108361","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ovarian cancer (OC) is a lethal malignancy often diagnosed at a late stage with frequent recurrence and immunotherapy resistance. PANoptosis is a novel programmed cell death regulating tumors and immunity. We constructed a prognostic model based on PANoptosis-related genes (PRGs) and evaluated its value for predicting immunotherapy response and survival in OC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>PRGs linked to OC prognosis were identified from public databases, followed by using the STRING database to develop a protein–protein interaction (PPI) network. The LASSO and multivariate Cox regression analyses were used to construct a risk model, and its predictive value was verified by survival analysis, receiver operator characteristic (ROC) curve, and nomogram. Next, we analyzed the immune microenvironment by combining CIBERSORT, MCP-counter, and ssGSEA algorithms and assessed the response of patients in different risk groups to immunotherapy using TIDE with immune phenotype score (IPS) methods. GSEA was performed to evaluate the activation status of biological pathways between patients in different risk groups. Finally, we verified the expression and potential biological functions of the key genes using quantitative reverse transcription-PCR (qRT-PCR), CCK-8, scratch, and transwell assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A PANoptosis-related risk model for OC was constructed based on eight genes (<i>PIK3CG</i>, <i>CAMK2A</i>, <i>CD38</i>, <i>NFKB1</i>, <i>PSMA4</i>, <i>PSMA8</i>, <i>PSMB1</i>, and <i>STAT4</i>). The model could accurately evaluate the prognostic outcomes for OC patients, showing a high stability across different datasets. High-risk patients had lower immune cell infiltration, elevated TIDE, and reduced IPS, which suggested weaker immunotherapy responsiveness and therefore a worse prognosis. In addition, pathway analysis showed that the high-risk group was mainly enriched in tumor progression–related pathways. In vitro, <i>PIK3CG</i>, <i>CAMK2A</i>, <i>NFKB1</i>, <i>PSMA4</i>, and <i>PSMB1</i> were upregulated in OC cell lines, and knockdown of <i>PIK3CG</i> notably suppressed the proliferative, migratory, and invasive capabilities of OC cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The PRG model established in this study may contribute to the assessment of immunotherapeutic response and prognosis for OC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7108361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145317439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Algorithm for Monogenic Noninvasive Prenatal Testing With Highly Similar Parental Pathogenic Haplotypes: A Representative Case of Congenital Adrenal Hyperplasia Pedigree","authors":"Wenjing Zhou,&nbsp;Fulin Liu,&nbsp;Shaojun Li,&nbsp;Di Wu,&nbsp;Jiyun Yang","doi":"10.1155/humu/9990873","DOIUrl":"https://doi.org/10.1155/humu/9990873","url":null,"abstract":"<p>Noninvasive prenatal testing (NIPT) has been widely used in various monogenic recessive disorders based on relative haplotype dosage (RHDO) analysis. We accepted a congenital adrenal hyperplasia (CAH) pedigree with highly similar parental pathogenic haplotypes. The initial monogenic NIPT attempt was unsuccessful due to a paucity of informative single-nucleotide polymorphisms (SNPs), prompting improvement of the current method. With a refined algorithm that deduces the fetal genotype based on dosage changes at SNPs located on a specific parental haplotype, while also effectively sidestepping allele bias introduced by hybrid capture, monogenic NIPT was successfully carried out in this family, yielding results consistent with invasive prenatal diagnosis. Theoretically, this algorithm can be employed in scenarios involving consanguineous marriages or when parents share a highly homologous haplotype, thereby broadening its applicability. Detailed methodology is described, and the advantages of our algorithm are discussed.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9990873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145316847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AIF1L as a Ferroptosis-Linked Biomarker in Microsatellite States–Driven Colorectal Cancer: Functional and Diagnostic Insights From Multiomics Analysis","authors":"Yuanyuan Qin,&nbsp;Hongli Zhou,&nbsp;Lingyan Zhu,&nbsp;Wenting Li,&nbsp;Zequn Jiang,&nbsp;Li Li,&nbsp;Mianhua Wu","doi":"10.1155/humu/6663166","DOIUrl":"https://doi.org/10.1155/humu/6663166","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Microsatellite instability (MSI) serves as a crucial biomarker for immune checkpoint blockade therapy in colorectal cancer (CRC). However, only around 40% of MSI CRC patients benefit from ICB. Investigating the mechanisms underlying MSI CRC, particularly its association with cell death and the immune microenvironment, can provide insights to improve immunotherapy efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Transcriptomic and clinical data of MSI CRC patients were collected from TCGA and GEO databases. Differential expression analysis, weighted gene coexpression network analysis, and Cox regression models were employed to identify five cell death–related prognostic genes (POU4F1, AIF1L, SLC18A1, INSL4, and HOXC6). Single-cell analysis, immune infiltration analysis, and in vitro and in vivo experiments were conducted to validate their roles in MSI CRC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The five-gene risk model effectively stratified high- and low-risk groups and predicted survival differences (AUC &gt; 0.6). AIF1L exhibited elevated expression in MSI-H groups and demonstrated a significant correlation with ferroptosis and immune cell infiltration. In vitro experiments showed that AIF1L boosted cell proliferation and migration via modulating ferroptosis, showing correspondence with in vivo experiments. Moreover, enrichment analysis revealed that AIF1L participated in immune-related signaling pathways, potentially impacting the tumor microenvironment and patient prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>AIF1L may regulate MSI CRC progression by promoting ferroptosis, serving as a prospective biomarker for prognosis and a therapeutic target for personalized therapy. This study uncovers new mechanisms in MSI CRC and provides a foundation for optimizing immunotherapy, though further investigation into its specific roles is needed.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6663166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145272553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One-Sided Matching Portal (OSMP): A Tool to Facilitate Rare Disease Patient Matchmaking","authors":"Matthew Osmond,&nbsp;E. Magda Price,&nbsp;Orion J. Buske,&nbsp;Mackenzie Frew,&nbsp;Madeline Couse,&nbsp;Taila Hartley,&nbsp;Conor Klamann,&nbsp;Hannah G. B. H. Le,&nbsp;Jenny Xu,&nbsp;Delvin So,&nbsp;Anjali Jain,&nbsp;Kevin Lu,&nbsp;Kevin Mo,&nbsp;Hannah Wyllie,&nbsp;Erika Wall,&nbsp;Hannah G. Driver,&nbsp;Warren A. Cheung,&nbsp;Ana S. A. Cohen,&nbsp;Emily G. Farrow,&nbsp;Isabelle Thiffault,&nbsp;Care4Rare Canada Consortium,&nbsp;Andrei L. Turinsky,&nbsp;Tomi Pastinen,&nbsp;Michael Brudno,&nbsp;Kym M. Boycott","doi":"10.1155/humu/5941599","DOIUrl":"https://doi.org/10.1155/humu/5941599","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Genomic matchmaking—the process of identifying individuals with overlapping phenotypes and rare variants in the same gene—is an important tool facilitating gene discoveries for unsolved rare genetic disease (RGD) patients. Current approaches are two-sided, meaning both patients being matched must have the same candidate gene flagged. This limits the number of RGD patients eligible for matchmaking. One-sided matchmaking, in which a gene of interest is queried in the genome-wide sequencing data of RGD patients, would make matchmaking possible for previously undiscoverable individuals. However, platforms and workflows for this approach have not been well established.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>We released a beta version of the One-Sided Matching Portal (OSMP), a platform capable of performing one-sided matchmaking queries across thousands of participants stored in genomic databases. The OSMP returns variant-level and participant-level information on each variant occurrence (VO) identified in a queried gene. A workflow for one-sided matchmaking was developed so that researchers could prioritize the many VOs returned from a given query. This workflow was tested through pilot studies where two sets of genes were queried in over 2500 individuals: 130 genes that were newly associated with disease in OMIM and 178 novel candidate genes that were not associated with a disease-gene association in OMIM. These pilots returned a large number of initial VOs (12,872 and 20,308, respectively); however, the workflow filtered out over 99.8% of these VOs prior to review by a participant’s clinician. Filters on participant-level information, including variant zygosity, participant phenotype, and whether a variant was also present in unaffected participants, were effective at reducing the number of false positive matches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>As demonstrated through the two pilot studies, one-sided matchmaking queries can be efficiently performed using the OSMP. The availability of variant-level and participant-level data is key to ensuring this approach is practical for researchers.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/5941599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145272309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polycystic Ovary Syndrome May Be Associated With a Novel Mitochondrial tRNAAsp Mutation","authors":"Yu Ding,&nbsp;Xuejiao Yu,&nbsp;Jian Xu,&nbsp;Caijuan Zhang,&nbsp;Jianhang Leng","doi":"10.1155/humu/6663471","DOIUrl":"https://doi.org/10.1155/humu/6663471","url":null,"abstract":"<p>Polycystic ovary syndrome is a common clinical condition often linked to insulin resistance (IR) and primarily affects women at reproductive age. Previous research has indicated a close association between mitochondrial tRNA (mt-tRNA) mutations and this syndrome; however, the range of mt-tRNA mutations in PCOS-IR remains largely unclear. In this study, we examined mt-tRNA mutations in 302 Han Chinese women with PCOS-IR and 589 control subjects, identifying a novel m.7544C&gt;T mutation potentially related to this syndrome. At the molecular level, the m.7544C&gt;T mutation occurs at a highly conserved nucleotide within the anticodon stem of mt-tRNA^Asp, disrupting the 30C-40G base-pairing. Using cybrids cells derived from two individuals carrying this mutation and two controls without it, we observed that the m.7544C&gt;T decreased the steady-state levels of tRNA^Asp, altered mitochondrial RNA transcripts, impaired the activities of respiratory chain enzymes and oxygen consumption rates (OCRs), compromised mitochondrial functions, and increased oxidative stress. Overall, our findings strongly suggest that the m.7544C&gt;T mutation contributes to the development of PCOS-IR, offering new insights into the pathophysiology of PCOS-IR driven by tRNA mutation–induced mitochondrial dysfunction and oxidative stress.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6663471","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity”","authors":"","doi":"10.1155/humu/9879845","DOIUrl":"https://doi.org/10.1155/humu/9879845","url":null,"abstract":"<p>S. Zhao, X. Lin, Y. Huang, et al., “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity,” <i>Human Mutation</i> 2025 (2025): 8369299, https://doi.org/10.1155/humu/8369299.</p><p>In the article titled “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity,” there were errors in all the affiliations. The corrected affiliation list appears below:</p><p>Shu Zhao,^1,2,3,4 Xiaojing Lin,^1,3 Yuying Huang,² Zhongmin Kang,⁵ Huali Luo,² Qizhu Zhang,^1,3 Qinshan Li,^1,2,3 and Mengxing Li⁵</p><p><i>¹Department of Obstetrics and Gynecology, Institute of Precision Medicine of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China</i></p><p><i>²Department of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, China</i></p><p><i>³Clinical Medical College, Guizhou Medical University, Guiyang, Guizhou, China</i></p><p><i>⁴Department of Obstetrics, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China</i></p><p><i>⁵Department of Hematology, Guizhou Province Institute of Hematology, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Affiliated Hospital of Guizhou Medical University Guiyang, Guizhou, China</i></p><p>We apologize for this error.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9879845","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complementary Roles of Structure and Variant Effect Predictors in RyR1 Clinical Interpretation","authors":"Rolando Hernández Trapero,&nbsp;Mihaly Badonyi,&nbsp;Lukas Gerasimavicius,&nbsp;Joseph A. Marsh","doi":"10.1155/humu/1834898","DOIUrl":"https://doi.org/10.1155/humu/1834898","url":null,"abstract":"<p>RyR1-related disorders, arising from variants in the RYR1 gene encoding the skeletal muscle ryanodine receptor, encompass a wide range of dominant and recessive phenotypes. The extensive length of RyR1 and diverse mechanisms underlying disease variants pose significant challenges for clinical interpretation, exacerbated by the limited performance and biases of current variant effect predictors (VEPs). This study evaluates the efficacy of 70 VEPs for distinguishing pathogenic RyR1 missense variants from putatively benign variants derived from population databases. Existing VEPs show variable performance. Those trained on known clinical labels show greater classification performance, but this is likely inflated by data circularity. In contrast, VEPs using methodologies that avoid or minimise training bias show limited performance, likely reflecting difficulty in identifying gain-of-function variants. Leveraging protein structural information, we introduce Spatial Proximity to Disease Variants (SPDV), a novel metric based solely on three-dimensional clustering of pathogenic mutations. We determine ACMG/AMP PP3/BP4 classification thresholds for our method and top-performing VEPs, allowing us to assign PP3/BP4 evidence levels to all RyR1 missense variants of uncertain significance. Thus, we suggest that our protein structure–based approach represents an orthogonal strategy over existing computational tools for aiding in the diagnosis of RyR1-related diseases.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1834898","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}