Human Mutation最新文献

{"title":"Potentially Deleterious Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in the Human MCPH1 Gene: Systematic In Silico Predictions and Implications for Structure and Function","authors":"Rizwana Kousar, Sadia Latif, Mohammed Turki Hussain Alharthi, Sidra Tabassum, Muzammil Ahmad Khan, Abdulfatah M. Alayoubi, Morad Qarmali, Muhammad Latif","doi":"10.1155/humu/3241521","DOIUrl":"10.1155/humu/3241521","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The <i>microcephalin 1</i>/<i>BRITI1</i> (<i>MCPH1</i>) gene has been implicated in microcephaly (MCPH), primary ciliary dyskinesia (PCD) syndrome, enlarged cranial volume, and pancreatic and breast cancers. It functions as a tumor suppressor and shows reduced expression in various cancer types. Therefore, the identification of <i>MCPH1</i> polymorphisms is of paramount importance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims and Objectives</h3>\u0000 \u0000 <p>Considering the multifaceted role of <i>MCPH1</i>, this study is aimed at examining the structural and functional impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) on <i>MCPH1</i> using in silico tools to understand its potential role in pathogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methodology</h3>\u0000 \u0000 <p>In the present investigation, a wide array of in silico tools was deployed to explicate putative pathogenic missense/nsSNPs that might impact the structural integrity and molecular functions of <i>MCPH1</i>. The mining of damaging nsSNPs was carried out based on the evolutionary conservation of sequence information, prediction of protein stability, interaction analysis, and their potential impact was assessed using structure prediction and 3D modeling, and interaction with other genes/pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the initial screening, SIFT, PolyPhen-2, SNAP2, Align GVGD, PhD-SNP, PANTHER, and SNPs&GO revealed 23 potential deleterious SNPs in <i>MCPH1</i>. Population frequency analysis using gnomAD revealed that the prioritized variants were extremely rare in the global population. I-mutant and ConSurf further revealed that 16 nsSNPs exhibited a decrease in protein stability due to changes in size and charge. I-TASSER was used to predict wild-type and mutant protein 3D structures. The potential effect of variation on 3D protein structure was assessed using the Chimera tool, which presented the probable structural loss in eight variants, including p.A11D, p.H49D, p.T59I, p.W60S, p.W60C, p.L74P, p.C79G, and p.L781P. Most of these potential variants resided in the <i>N</i>-terminal BRCT domain, which is implicated in neurodevelopment, and thus may lead to the pathogenesis of primary microcephaly. Furthermore, single-cell transcriptomic mapping of MCPH1 against dataset of 33,206 cells from malformations of cortical development detected MCPH1 expression across multiple cellular populations. This broad distribution suggested potential MCPH1 function across several neural and glial cell populations.</p>\u0000 </section>\u0000 \u0000 ","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887327","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":"Phenotypes of Hereditary Diseases Associated With Rauch–Steindl Syndrome","authors":"Yi Kong,&nbsp;Yousheng Wang,&nbsp;Xingwang Wang,&nbsp;Li Guo,&nbsp;Jianhong Chen,&nbsp;Yan Ji,&nbsp;Jiaolan Liu,&nbsp;Wanfang Xu,&nbsp;Weiling Du,&nbsp;Haiyan Wang,&nbsp;Yan Zhang","doi":"10.1155/humu/1637135","DOIUrl":"10.1155/humu/1637135","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Prenatal phenotypic manifestations of genetic disorders associated with <i>NSD2</i> variants remain poorly characterized. This study presents our institutional experience with the prenatal diagnosis of <i>NSD2</i>-associated genetic disorders, specifically Rauch–Steindl syndrome (RAUST), aiming to improve understanding of both the molecular and clinical features of RAUST.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a retrospective analysis of six fetuses and one adult diagnosed with RAUST at our institution and thoroughly reviewed the prenatal ultrasound reports of six fetuses. Prenatal and postnatal phenotypes of RAUST cases were summarized alongside findings from previously published literature. Correlations between NSD2 variant locations, variant types, and phenotypes were analyzed. Additionally, protein modeling was used to visualize structural changes in NSD2 protein before and after C-terminal variants. We integrated single-cell transcriptomic and gene expression data from multiple public databases to investigate spatiotemporal expression patterns of <i>NSD2</i> during human fetal development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Fetal growth restriction (FGR) was the most prevalent prenatal manifestation in RAUST fetuses, followed by microcephaly. Bilateral renal hypoplasia emerged as a novel prenatal ultrasonographic feature. Postnatally, speech and motor developmental delays were the most commonly reported phenotypes, followed by physical developmental delays and intellectual disability. Genotype-phenotype correlation analysis revealed an association between N-terminal truncating variants in NSD2 and impaired fetal growth parameters. Notably, C-terminal truncating variants—predicted not to directly impact NSD2 functional domains—also exerted disease-causing effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study provides a comprehensive analysis of prenatal phenotypes in RAUST cases, enriching the prenatal phenotypic spectrum of the disease and facilitating early diagnosis and clinical management of RAUST. Furthermore, our genotype-phenotype correlation findings lay a foundational basis for future research into the complex molecular mechanisms underlying <i>NSD2</i>-associated genetic disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887342","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":"MYC-Driven LDHA/PABPC1/PLK1 Model Predicts Prognosis, Immune Landscape, and Therapeutic Response in Lung Adenocarcinoma","authors":"Tianwei Xu,&nbsp;Lihua Jiang,&nbsp;Shuai Yan,&nbsp;Jing Zhang,&nbsp;Ligong Chang,&nbsp;Yingying Qian,&nbsp;Jiankang Xu","doi":"10.1155/humu/5792218","DOIUrl":"https://doi.org/10.1155/humu/5792218","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;MYC is a central oncogenic driver in lung adenocarcinoma (LUAD), coordinating proliferation, metabolism, and immune evasion. However, LUAD lacks a MYC-anchored prognostic framework that jointly relates survival risk to pathway activity, immune contexture, and potential therapeutic response. This study is aimed at developing and validating such multidimensional model and determining whether it captures clinically and biologically relevant heterogeneity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We first obtained LUAD transcriptome and clinical data from public databases, along with the HALLMARK_MYC_TARGETS_V1 and HALLMARK_MYC_TARGETS_V2 gene sets from the Molecular Signatures Database (MSigDB). Subsequently, enrichment analysis was performed using gene set enrichment analysis (GSEA), and differentially expressed genes (DEGs) were screened using the DESeq2 package. A MYC-related prognostic model was constructed using univariate Cox analysis and LASSO, followed by multivariate Cox regression. Immune infiltration, pathway enrichment, TIDE-based immunotherapy prediction, and GDSC2-based drug sensitivity were compared between high- and low-risk groups. Seurat was used to process single-cell RNA sequencing (scRNA-seq) data and map cell type-specific expression of key genes. Finally, we validated the expression and potential functions of the screened key genes using in vitro LUAD cells lines.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We identified 41 genes that are differentially expressed and associated with MYC in LUAD, and from these, we constructed a three-gene prognostic model driven by MYC, comprising lactate dehydrogenase A (&lt;i&gt;LDHA&lt;/i&gt;), poly(A)-binding protein cytoplasmic 1 (&lt;i&gt;PABPC1&lt;/i&gt;), and polo-like kinase 1 (&lt;i&gt;PLK1&lt;/i&gt;). High-risk tumors were enriched for MYC targets, E2F targets, G2/M checkpoint, DNA replication, and chromosome-segregation programs. They also showed distinct immune infiltration patterns, higher TIDE scores, and differential predicted sensitivity to multiple anticancer agents. Single-cell analysis revealed heterogeneous expression of &lt;i&gt;LDHA&lt;/i&gt; and &lt;i&gt;PABPC1&lt;/i&gt; across tumor and stromal compartments, whereas &lt;i&gt;PLK1&lt;/i&gt; was not detectably expressed. In vitro, &lt;i&gt;LDHA&lt;/i&gt;, &lt;i&gt;PABPC1&lt;/i&gt;, and &lt;i&gt;PLK1&lt;/i&gt; were upregulated in A549 cells compared with BEAS-2B cells, and &lt;i&gt;LDHA&lt;/i&gt; knockdown significantly impaired A549 cell invasion and migration.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The MYC-related three-gene model provides a discovery-stage framework for linking prognosis with pa","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/5792218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942244","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":"SP1-Driven SPP1+ Senescent Macrophages Orchestrate an Immunosuppressive Microenvironment in Triple-Negative Breast Cancer","authors":"Yuting Liu,&nbsp;Jingjing Zhang,&nbsp;Shuangyue Liu,&nbsp;Xiaozhang Xu,&nbsp;Xin Meng,&nbsp;Xintong Wang,&nbsp;Zhipeng Wang,&nbsp;Linlin Zhen,&nbsp;Yi Ren","doi":"10.1155/humu/7561241","DOIUrl":"https://doi.org/10.1155/humu/7561241","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Cellular senescence is a complex biological process that profoundly influences tumor progression and the remodeling of the tumor microenvironment (TME). Although its biological impact as a hallmark of cancer is becoming increasingly understood across various malignancies, the specific role of cellular senescence in driving the immunosuppressive landscape of triple-negative breast cancer (TNBC) remains to be fully elucidated.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We integrated multiple publicly available bulk transcriptomic datasets (TCGA, METABRIC, and GSE76250) with single-cell RNA sequencing (scRNA-seq) data to identify senescence-related signatures in TNBC. A comprehensive bioinformatic framework, encompassing differential expression analysis, functional enrichment analysis, pseudotime trajectory analysis, transcription factor activity analysis, virtual knockout analysis, cell–cell interaction analysis, and spatial transcriptomics colocalization analysis was employed to characterize and validate the potential associations of cellular senescence with the immunosuppressive microenvironment and clinical significance in TNBC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We identified a 10-gene TNBC senescence signature that serves as an independent prognostic factor, wherein higher signature scores correlated with significantly worse overall survival and an exhausted immune microenvironment. Single-cell analysis revealed specific SPP1&lt;sup&gt;+&lt;/sup&gt; macrophages as the primary carriers of senescence activation within the TME. These SPP1&lt;sup&gt;+&lt;/sup&gt; senescent macrophages exhibit a distinct metabolic profile characterized by enhanced glycolysis and hypoxia signaling. Mechanistically, we identified the transcription factor SP1 as a core regulator driving the senescent phenotype of SPP1&lt;sup&gt;+&lt;/sup&gt; senescent macrophages by directly modulating the expression of CDKN1A and SPP1. Furthermore, cell–cell interaction and spatial transcriptomic analyses revealed that SPP1&lt;sup&gt;+&lt;/sup&gt; senescent macrophages orchestrate an immunosuppressive niche by recruiting exhausted PDCD1&lt;sup&gt;+&lt;/sup&gt; CD8&lt;sup&gt;+&lt;/sup&gt; T cells via the CXCL12-CXCR4 axis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study characterizes a novel senescence landscape in TNBC, which is driven by SPP1&lt;sup&gt;+&lt;/sup&gt; senescent macrophages. Our findings highlight the SP1-driven SPP1&lt;sup&gt;+&lt;/sup&gt; macrophage senescence axis as a crucial driver of the immunosuppressive and exhausted TME in TNBC, suggesting it is a promising therapeutic target for future clinical interven","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7561241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942126","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":"Functional Validation of a Novel Homozygous TTN Splice-Site Variant Reveals Aberrant Splicing in Hypertrophic Cardiomyopathy","authors":"Xiaoyun Sun,&nbsp;Dandan Wang,&nbsp;Shujuan Wang,&nbsp;Rong Wan,&nbsp;Zhenhong Jiang,&nbsp;Wenqiang Zhang,&nbsp;Jin Ouyang,&nbsp;Yang Shen,&nbsp;Kui Hong","doi":"10.1155/humu/4229370","DOIUrl":"10.1155/humu/4229370","url":null,"abstract":"<p>The <i>TTN</i> gene encodes a crucial structural protein within cardiac sarcomeres, and its variants may contribute to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy; however, phenotype and genotype are different. Whole-exome sequencing (WES) was conducted on a Chinese proband diagnosed with HCM. In silico splicing prediction tools and minigene assays were employed to investigate the impact of the identified variant on mRNA splicing. A literature review was performed to retrieve and analyze previously reported splicing variants in the <i>TTN</i> gene associated with HCM. A 42-year-old male proband presented with nonobstructive HCM and paroxysmal atrial arrhythmias. A novel homozygous <i>TTN</i> variant was found, predicted to cause a 14-base pair deletion at a splice acceptor site. Two asymptomatic offspring were found to carry the heterozygous variant. Based on variant interpretation guidelines, the variant met the PM2_supporting criterion and was classified as a variant of uncertain significance (VUS). The predicted aberrant splicing effect was subsequently confirmed by the minigene splicing assay, demonstrating altered pre-mRNA splicing leading to an in-frame insertion/deletion (p.Arg32498_Glu32504delinsGln). Functional verification confirmed that this mutation conforms to the PM4 criterion, suggesting that it can be reclassified as a tepid VUS (scoring 3 points). The functional result might provide pathogenic evidence. We also reviewed 28 previously reported splicing variants in <i>TTN</i> associated with HCM. Of these, 57.1% (16/28) localized to the I-band region, whereas 21.4% (6/28) were situated in the A-band domain of titin. Notably, 21.4% (6/28) co-occurred with pathogenic variants in other sarcomeric genes (<i>MYH7</i> or <i>MYBPC3</i>), correlating with more severe clinical phenotypes. Reclassification and reinterpretation of the variants revealed that none met the level of likely pathogenic or higher. The present case contributes a homozygous splice-site variant with experimentally confirmed aberrant splicing and an in-frame protein alteration in titin. The focus of this report is the Mendelian genetic basis of the proband′s cardiomyopathy phenotype, and our data provide additional case-level and functional evidence for a possible role of specific <i>TTN</i> splicing defects in HCM.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13542574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897061","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":"Integrative Multiomics Analysis of HLA-DMB in Glioblastoma Reveals Biomarker Potential and Immune Landscape","authors":"Nan Lu,&nbsp;Qian Guo,&nbsp;Xiyuan Zhu,&nbsp;Taoyu Zhu,&nbsp;Xutong Xue,&nbsp;Cristiano Coppola,&nbsp;Kaijun Zhao,&nbsp;Yu′e Liu","doi":"10.1155/humu/2090334","DOIUrl":"https://doi.org/10.1155/humu/2090334","url":null,"abstract":"<p>Glioblastoma (GBM) remains one of the most aggressive brain tumors, with limited treatment options and poor prognosis. Advances in computational biology have enabled the identification of novel biomarkers for improved diagnosis and therapy. In this study, we investigate the role of antigen presentation gene HLA-DMB in GBM using a multiomics approach integrating single-cell RNA sequencing, bulk transcriptomics, survival analysis, and machine learning. Differential expression analysis identified HLA-DMB as a key gene associated with GBM. Machine learning algorithms, including LASSO regression and random forest, consistently ranked HLA-DMB as a top feature. Survival analysis revealed that high HLA-DMB expression is independently associated with poor progression-free interval (PFI), whereas associations with overall survival and disease-specific survival did not reach statistical significance. Functional enrichment analysis linked HLA-DMB to apoptosis, cell cycle regulation, and immune-related pathways. Single-cell analysis demonstrated that HLA-DMB is primarily expressed in M1 macrophages, suggesting a role in tumor immunity. Immune infiltration analysis further confirmed its association with tumor-associated macrophages, fibroblasts, and T-cell activation. Drug sensitivity analysis using Connectivity Map (CMAP) identified potential compounds targeting HLA-DMB. Overall, our findings identify HLA-DMB as a candidate biomarker for GBM, providing insights that may inform future prognostic and therapeutic investigations.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/2090334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148942055","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":"Human Variation-Informed Prioritization of MPHOSPH6 in Lung Adenocarcinoma: A Source-Aware Multiomics Evidence Framework","authors":"Chongwen Fang,&nbsp;Min Wu,&nbsp;Jing Lv,&nbsp;Yanping Zhang,&nbsp;Qinyun Zheng,&nbsp;Xiang Shen,&nbsp;Shangke Huang","doi":"10.1155/humu/1879922","DOIUrl":"10.1155/humu/1879922","url":null,"abstract":"<p>Moving from an association signal to a clinically credible biomarker requires several links that are often conflated: verified variant identity, aligned allelic effects, reproducible gene-level association, relevant cellular expression, and a plausible functional consequence. We developed a source-aware multiomics framework to assess MPHOSPH6 in lung adenocarcinoma (LUAD) while keeping those evidence classes separate. Six prespecified rsIDs were recovered from the harmonized TRICL LUAD dataset, of which five reached <i>p</i> &lt; 5 × 10 − 8. Only rs112333466 and rs76474922 were available with alignable alleles in FinnGen R10, and both showed concordant directions. Fixed-effect estimates were OR = 1.592 for rs112333466-T (95% CI, 1.401–1.809; <i>p</i> = 9.91 × 10 − 13) and OR = 0.819 for rs76474922-C (95% CI, 0.773–0.867; <i>p</i> = 1.03 × 10 − 11). In a prespecified two-variant GTEx v8 lung model, genetically predicted MPHOSPH6 expression was positively associated with LUAD in TRICL (<i>Z</i> = 3.341, <i>p</i> = 8.35 × 10 − 4) and FinnGen (<i>Z</i> = 2.697, <i>p</i> = 0.0070). This gene-level result did not establish colocalization or connect MPHOSPH6 to the six susceptibility rsIDs. Patient-level analysis of 89,241 immune cells from six paired tumor and normal-adjacent lung samples found no significant difference in MPHOSPH6 pseudobulk abundance (exact paired Wilcoxon <i>p</i> = 0.3125). None of 688 lung-lineage pharmacogenomic tests remained significant after false-discovery-rate correction. Ten recorded MPHOSPH6 missense alleles, including five ClinVar variants of uncertain significance, were curated; structural analysis identified I58 at an experimental RNA-exosome interface and defined a focused perturbation series. MPHOSPH6 is therefore supported as a human–variation-informed candidate for functional evaluation, not as a validated LUAD biomarker, pathogenic gene, drug-response predictor, or therapeutic target.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880067","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":"Integrated Multiomics Analysis Links PAH-Associated Molecular Features to Somatic Mutation and Genomic Complexity in Pancreatic Ductal Adenocarcinoma","authors":"Peng Wang,&nbsp;Shi Huang,&nbsp;Wenjing Chen,&nbsp;Guanghui Tao,&nbsp;Yicheng Shen,&nbsp;Xuebing Shi","doi":"10.1155/humu/9549681","DOIUrl":"https://doi.org/10.1155/humu/9549681","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Polycyclic aromatic hydrocarbons (PAHs) have mutagenic and carcinogenic potential, but their relationships with genomic alterations and epithelial and stromal heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We integrated network toxicology, pathomics, bulk, single cell, and spatial transcriptomics, immune phenotyping, protein expression, virtual knockout analysis, genomic profiling, and molecular docking. PAH-associated PDAC target genes were linked to ductal epithelial cell (DEC) and cancer associated fibroblast (CAF) states. RAC1 associated somatic mutations, tumor mutation burden (TMB), copy number alterations (CNAs), and mutational signatures were further characterized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Ninety-one PAH-associated PDAC target genes were identified. CTSG, PRKCB, PTPN7, and SMO formed a four-gene PAH-associated PDAC target derived protective gene set (PPTP gene set) associated with favorable prognosis and a stable DEC state, whereas high RAC1 expression was associated with poor prognosis and CAF remodeling. Tumors with high RAC1 expression showed higher TMB and enrichment of KRAS, TP53, CDKN2A, and SMAD4 alterations. RAC1 expression was positively associated with TMB, CNA burden, and mutational signature contributions and was higher in tumors with KRAS, TP53, or CDKN2A mutations. PPTP expression showed inverse associations with genomic complexity. Single-cell and spatial analyses linked RAC1 to CAF, DEC, and immune remodeling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>RAC1 expression and the PPTP signature identify distinct PDAC states with contrasting somatic mutation burden, driver alterations, copy number changes, mutational signature activity, and epithelial and stromal organization. These findings link somatic mutation and genomic complexity with microenvironmental heterogeneity in PDAC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9549681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849377","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":"Computational Characterization of Pathogenic LMNA Missense Variants: Structural Instability, Altered Binding, and Conformational Dynamics","authors":"Emre Aktaş,&nbsp;Ceren Nizamoğlu,&nbsp;Salvador Ventura","doi":"10.1155/humu/2444803","DOIUrl":"10.1155/humu/2444803","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Mutations in the &lt;i&gt;LMNA&lt;/i&gt; gene underlie a broad spectrum of laminopathies, including muscular dystrophies, cardiomyopathies, and premature aging syndromes; however, the molecular mechanisms by which missense variants disrupt Lamin A structural integrity remain incompletely characterized. Systematic computational approaches for prioritizing pathogenic variants and elucidating their structural consequences are critically needed.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;An integrated multistep in silico framework was employed to investigate the structural and functional consequences of &lt;i&gt;LMNA&lt;/i&gt; missense variants. Variant prioritization was performed using the Evo2 nucleotide language model via delta log-likelihood scoring, followed by bioinformatic annotation using SIFT, PANTHER-PSEP, PhD-SNP, and E-SNPs&amp;GO. Protein stability assessment was conducted with DynaMut, INPS-MD, I-Mutant2.0, and MUpro. Variants localized within globular domains—N456D, N456T, and G465D—together with the known pathogenic variant M540T as a positive control, were selected for three-dimensional structural modeling using PyMOL and AlphaFold2, molecular docking with lonafarnib as a reference ligand via AutoDock Vina, and 100 ns molecular dynamics simulations using GROMACS with the Amber ff14SB force field. Conformational dynamics were characterized through principal component analysis and free-energy surface construction.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Evo2-based screening of the full LMNA coding sequence identified 50 high-priority loss-of-function variants, of which N456D, N456T, and G465D were retained for structural investigation based on their globular domain localization and multitool pathogenicity predictions. All three variants were consistently predicted to alter physicochemical properties and reduce structural stability relative to wild-type Lamin A. Molecular docking revealed mutation-dependent changes in lonafarnib binding profiles. The known pathogenic control M540T exhibited comparable structural and dynamic behavior, supporting the reliability of the prioritization workflow. Molecular dynamics analyses demonstrated altered RMSD trajectories, increased residue-level flexibility, and modified hydrogen bonding patterns in mutant systems. Free-energy landscape analyses revealed expanded conformational basins, particularly pronounced in the G465D variant, indicating increased structural plasticity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This integrated computational framework provides a systematic strate","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148827844","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 PD-1-Related Genes as Prognostic Biomarkers in Lung Adenocarcinoma","authors":"Bin Jia,&nbsp;Ting Gong,&nbsp;Chen Chen,&nbsp;Bingsheng Sun,&nbsp;Zhenfa Zhang","doi":"10.1155/humu/8948469","DOIUrl":"10.1155/humu/8948469","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The PD-1/PD-L1 axis plays a critical role in suppressing T-cell activation and facilitating immune evasion in lung adenocarcinoma (LUAD). This study focused on PD-1-related genes to develop a robust prognostic prediction model for LUAD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Immune scores were calculated using the ESTIMATE algorithm, and immune-related gene modules were identified through WGCNA. Differentially expressed genes (DEGs) were identified between normal and tumor tissues, and between high and low PD-1 expression groups, using the limma package. Univariate and multivariate Cox regression analyses were performed to construct a prognostic risk model, which was subsequently evaluated using time-dependent ROC curve analysis with the timeROC package. Biomarker expression and function were validated in LUAD cells via western blot (WB), CCK-8, wound healing, and Transwell assays. Functional enrichment analysis was conducted using the clusterProfiler package. The tumor microenvironment (TME) was characterized by integrating MCPcounter, ESTIMATE, and ssGSEA. Drug sensitivity was predicted using the pRRophetic R package.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;WGCNA showed that genes in the brown module were significantly positively correlated with the immune score, and these genes were predominantly enriched in biological processes such as neutrophil activation and cytokine activity. By intersecting the brown module genes, DEGs, and PD-1-related genes, we constructed a risk prognosis model comprising nine key genes (&lt;i&gt;ADA2&lt;/i&gt;, &lt;i&gt;CD53&lt;/i&gt;, &lt;i&gt;HLA-DMA&lt;/i&gt;, &lt;i&gt;ITGAX&lt;/i&gt;, &lt;i&gt;MYO1F&lt;/i&gt;, &lt;i&gt;NCKAP1L&lt;/i&gt;, &lt;i&gt;PTPRC&lt;/i&gt;, &lt;i&gt;RENBP&lt;/i&gt;, and &lt;i&gt;TNFAIP8L2&lt;/i&gt;). The model demonstrated robust predictive performance, with high AUC values in time-dependent ROC analysis. Patients within the high-risk group exhibited a worse prognosis. Additionally, RiskScore for patients in the high-risk group was closely associated with immune infiltration, immune checkpoint expression, and drug sensitivity. The low-risk group exhibited higher levels of immune cell infiltration, including T cells, CD8&lt;sup&gt;+&lt;/sup&gt; T cells, and B lineage cells. Furthermore, in vitro experiments have demonstrated that silencing the representative gene &lt;i&gt;MYO1F&lt;/i&gt; significantly inhibited the migration and invasion of LUAD cells, whereas &lt;i&gt;PTPRC&lt;/i&gt; knockdown promoted these capacities. Drug sensitivity analysis identified distinct candidate therapeutic agents for the high- and low-risk groups.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In conclusion, thi","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13504365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817714","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}