Hum. Mutat. [JOURNAL]
Sun
200 papers
A Macrophage/Monocyte-Related Four-Gene Signature for Prognostic Assessment of Uveal Melanoma: , , , and .
Yu Y, Wang M, Zhao B
Hum Mutat · 2026 · PMID 42311235 · Full text
BACKGROUND: Uveal melanoma (UVM) is a highly malignant ocular tumor with a poor prognosis. Macrophages and monocytes in the tumor microenvironment promote immune escape, angiogenesis, and metastasis. Thus, exploring thei...
BACKGROUND: Uveal melanoma (UVM) is a highly malignant ocular tumor with a poor prognosis. Macrophages and monocytes in the tumor microenvironment promote immune escape, angiogenesis, and metastasis. Thus, exploring their roles may provide insights into UVM progression. METHODS: The Cancer Genome Atlas (TCGA) was accessed to obtain the data of mRNA expression and follow-up data of UVM, and UVM single-cell profiles were downloaded to cluster cells by annotation of single-cell marker genes. The differentially expressed genes (DEGs) in macrophage/monocyte cells compared to other cell types were revealed. ssGSEA was applied to compute the score of DEGs and to reveal the genes for WGCNA in UVM. A prognostic risk model for UVM was constructed by uni/multivariate Cox and LASSO regression analyses to reveal the differential overall survival status. Further cellular validations were conducted to examine the effects of core genes in UVM. TIMER tool was applied for the analysis of immune cell infiltration levels in UVM. Chemotherapeutic drug sensitivity in UVM was assessed with the pRRophetic package. RESULTS: Six cell subpopulations were identified in the UVM samples, among which macrophage/monocyte cells were more predominant. Kaplan-Meier curves showed that UVM patients in the group of high RiskScore (consisting of the genes , , , and ) presented a poorer prognosis, higher infiltration of monocytic lineage, T cells, CD8 T cells, cytotoxic lymphocytes, and higher expression of immune checkpoint-related genes. A significant negative correlation between RiskScore and the IC of XMD8-85, lapatinib, roscovitine, salubrinal, bexarotene, LFM-A13, FTI-277, and TGX221 chemotherapeutic agents was further noticed. CONCLUSION: In this study, we computationally identified genes associated with both disease progression and macrophage/monocyte-related characteristics in UVM and constructed a prognostic risk model with predicted immune infiltration patterns. These findings generate testable hypotheses that may inform future experimental studies on the immune mechanisms underlying UVM.
A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces.
Wu T, He F, Ni X … +2 more , Yin F, Peng J
Hum Mutat · 2026 · PMID 42311234 · Full text
Two clinical phenotypes are associated with GLUL mutations, from different inheritance mode. Recessive forms are associated with congenital glutamine deficiency, manifesting with severe brain malformation, multiorgan fai...
Two clinical phenotypes are associated with GLUL mutations, from different inheritance mode. Recessive forms are associated with congenital glutamine deficiency, manifesting with severe brain malformation, multiorgan failure, and early death. A dominant form has recently been described, which involves dysregulated glutamine synthetase stability and manifests as developmental and epileptic encephalopathy (DEE). All reported dominant mutations are within the start codon or the 5 UTR. Here, we report a DEE patient with a de novo variant, c.522_536dup, in the catalytic domain of GLUL. Her brain MRI demonstrated involvement of the white matter signal-intensity alterations and markedly enlarged perivascular spaces. In vitro overexpression assays revealed no difference in protein expression or enzyme activity between the mutant and wild-type under normal glutamine conditions. However, under either low or high glutamine concentrations, the mutant exhibited significantly higher enzyme activity than the wild-type, indicating disrupted regulation of glutamine synthetase activity. This study expands the spectrum of variants, provides further evidence for the role of enzyme stability in gain-of-function variants, and highlights enlarged perivascular spaces as a diagnostic clue in GLUL-related disorders.
Structural Variant and Repeat Expansion Findings Identified by Optical Genome Mapping in Complex Autism Spectrum Disorder With Concomitant Neurodevelopmental Disorders.
Mutlu MB, Öğütlü ÖBG, Öz Ö … +13 more , Duymuş F, Seyhan S, Tokaç AGB, Tezcan E, Öğütlü H, Demiryılmaz F, Silahtarlıoğlu N, Bilgil K, Elma S, Erdoğan M, Gümüş H, Kumandaş S, Kılıçaslan F
Hum Mutat · 2026 · PMID 42293335 · Full text
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, along with restricted, repetitive patterns of behavior, interests, or activiti...
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, along with restricted, repetitive patterns of behavior, interests, or activities. Single-nucleotide variants (SNVs) and structural variants (SVs), including copy-number variants (CNVs), have been reported as important contributors to the genetic basis of ASD. In this study, we evaluated the diagnostic contribution of optical genome mapping (OGM) as a complementary cytogenomic approach in a selected ASD cohort enriched for complex ASD with developmental delay/intellectual disability (DD/ID) and/or additional neurodevelopmental or syndromic features. We retrospectively evaluated 34 individuals with ASD who underwent OGM analysis, most of whom had concomitant DD/ID and/or additional neurological, congenital, or syndromic features. Confirmed pathogenic (P) or likely pathogenic (LP) findings were identified in 7/34 individuals (20.6%), and one additional unconfirmed OGM-only duplication was provisionally interpreted as pathogenic. Overall, confirmed or provisional P/LP findings were observed in 8/34 individuals (23.5%), all of whom had complex ASD with DD/ID and/or additional neurodevelopmental or syndromic features. OGM-detected findings were confirmed by orthogonal methods whenever clinically and technically feasible, and segregation analyses were performed when samples were available. These results suggest that OGM may add value to integrated genetic testing workflows for selected individuals with complex ASD, particularly when SVs, complex chromosomal rearrangements, or full-mutation repeat expansions are clinically suspected or insufficiently resolved by conventional approaches.
Molecular Subtyping Based on EGFR Mutation-Associated Genes and the Prognostic Role of TRAF2 in Lung Adenocarcinoma.
Gao B, Dong Z, Yan T … +2 more , Liu Z, Chen J
Hum Mutat · 2026 · PMID 42293334 · Full text
This study is aimed at systematically identifying key genes associated with EGFR mutations and developing a molecular classification model in lung adenocarcinoma (LUAD) using integrative bioinformatics approaches. Multi-...
This study is aimed at systematically identifying key genes associated with EGFR mutations and developing a molecular classification model in lung adenocarcinoma (LUAD) using integrative bioinformatics approaches. Multi-omics datasets derived from cBioPortal and The Cancer Genome Atlas (TCGA) LUAD cohort were interrogated to identify genes correlated with EGFR mutational status. A core set of 18 genes exhibiting significant associations with both EGFR mutation frequency and patient prognosis was identified. Based on this gene signature, a two-cluster molecular subtype stratification was established. These subtypes demonstrated statistically significant divergence in overall survival, immune cell infiltration profiles, and predicted responsiveness to immunotherapeutic intervention. Further analyses, including machine learning algorithms, multivariate Cox regression, and molecular docking, identified TRAF2 as a key prognostic gene closely associated with EGFR. In vitro experiments demonstrated that TRAF2 promotes proliferation, migration, and invasion of LUAD cells. Additional analyses suggested that TRAF2 may contribute to tumor progression through epigenetic regulation and associated signaling pathways. Collectively, these findings provide novel insights into the molecular heterogeneity of EGFR-mutant LUAD and offer potential targets for precision prognostic assessment and combination therapeutic strategies.
Resveratrol Ameliorates Diabetic Peripheral Neuropathy via the AMPK/mTOR/Bcl-2 Axis: Integrative Evidence From Network Pharmacology, Mendelian Randomization, and Binding-Site Evolutionary Constraint.
Zhang C, Mo G, Zhang Y … +3 more , Xu H, Hu X, Zhang J
Hum Mutat · 2026 · PMID 42293333 · Full text
BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common diabetic complication with unclear pathogenesis. Current therapies are limited, and resveratrol shows potential in DPN but its therapeutic mechanisms remain un...
BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common diabetic complication with unclear pathogenesis. Current therapies are limited, and resveratrol shows potential in DPN but its therapeutic mechanisms remain unclear. METHODS: Candidate targets and pathways were identified via network pharmacology and protein-protein interaction analysis. Two-sample MR was performed using eQTL and GWAS data to assess causal associations of PRKAA1, PRKAA2, MTOR, and BCL2 with DPN. Molecular docking was used to characterize ligand-target interactions, followed by mutational constraint analysis based on gnomAD to evaluate evolutionary conservation of binding-site residues. Functional validation was conducted in streptozotocin (STZ)-induced DPN mice and high-glucose-treated RSC96 Schwann cells and RAW264.7 macrophages, assessing nerve function, oxidative stress, apoptosis, and macrophage polarization. RESULTS: Resveratrol significantly improved motor nerve conduction velocity, sensory function, and sciatic nerve integrity in DPN mice, while reducing oxidative stress and neuronal apoptosis. It promoted M2 macrophage polarization, with increased IL-10 and decreased TNF- levels. Network analysis identified the AMPK/mTOR/Bcl-2 axis as a central pathway. MR supported MTOR as a risk factor and BCL2 and PRKAA1 as protective factors for DPN. Mutational constraint analysis revealed marked depletion of missense variants and higher pathogenicity scores in resveratrol-binding residues of MTOR and BCL2, indicating strong evolutionary constraint. Integration of genetic, structural, and functional evidence consistently prioritized MTOR and BCL2 as key targets. CONCLUSIONS: Resveratrol alleviates DPN by modulating oxidative stress, apoptosis, and neuroinflammation via the AMPK/mTOR/Bcl-2 axis and macrophage polarization. The integration of causal inference and binding-site evolutionary constraint strengthens target validity and highlights resveratrol as a multitarget therapeutic candidate.
SRSF1/Mcl-1 Axis Drives Apoptosis Evasion and Shapes the Immune Microenvironment to Promote Gastric Cancer Progression.
Liu X, Liu D, Zhang G … +2 more , Liu S, Cai H
Hum Mutat · 2026 · PMID 42293332 · Full text
Gastric cancer (GC) is one of the malignancies with the highest incidence and mortality worldwide. Evasion of apoptosis is a hallmark of cancer that drives tumor progression. The splicing factor SRSF1 and antiapoptotic p...
Gastric cancer (GC) is one of the malignancies with the highest incidence and mortality worldwide. Evasion of apoptosis is a hallmark of cancer that drives tumor progression. The splicing factor SRSF1 and antiapoptotic protein Mcl-1, including its isoforms Mcl-1L and Mcl-1S, play significant roles in cancer development; however, the regulatory mechanisms of the SRSF1-Mcl-1 axis in GC remain unclear. This study systematically evaluated the function of SRSF1 in GC by integrating multidatabase analyses (TIMER, UALCAN, and KM-Plotter), in vitro experiments (qRT-PCR, Western blot, Transwell migration/invasion, and apoptosis assays), in vivo xenograft models, and bioinformatic approaches (single-cell RNA sequencing, hdWGCNA, cell interaction analysis, and mutational analysis). SRSF1 is significantly overexpressed in GC tissues and cell lines, correlating with poor prognosis in patients. Through comprehensive multiomics analysis, we first revealed that SRSF1-positive malignant epithelial cells possess a unique coexpression network and exhibit significantly enhanced interactions with fibroblasts, reshaping the tumor microenvironment (TME). Subsequently, functional assays demonstrated that SRSF1 overexpression enhances cell invasion, migration, and apoptosis resistance by inhibiting the proapoptotic isoform Mcl-1S and suppressing the mitochondrial apoptosis pathway (Bak/caspase-9/caspase-3). In conclusion, the SRSF1-Mcl-1 axis serves as a dual key regulator of invasion/migration and apoptosis evasion in GC, providing a new strategy for targeted therapy in advanced GC.
CLEC4G Promotes Pancreatic Cancer Progression by Suppressing Cathepsin B-Mediated Ferroptosis: Evidence From Mendelian Randomization Study and Experimental Validation.
Jiang Z, Ma P, Zhang S … +9 more , Jin Z, Wang Y, Zhou Y, Zhu Q, Lu C, Tu N, Zhang ZA, Mou Y, Jin W
Hum Mutat · 2026 · PMID 42282992 · Full text
Pancreatic cancer (PC) is highly lethal and lacks causal biomarkers that can inform mechanism-based therapies. Ferroptosis is an iron-dependent form of regulated cell death implicated in PC, but upstream determinants of...
Pancreatic cancer (PC) is highly lethal and lacks causal biomarkers that can inform mechanism-based therapies. Ferroptosis is an iron-dependent form of regulated cell death implicated in PC, but upstream determinants of ferroptosis in PC remain unclear. We integrated large-scale proteomic quantitative trait locus (pQTL) resources with Mendelian randomization (MR) and cell-based experiments to identify causal regulators of ferroptosis relevant to PC. Using two-sample MR with plasma pQTL data from the deCODE cohort and the UK Biobank Pharma Proteomics Project and PC genome-wide association summary statistics from FinnGen, we screened 159 FerrDb-defined ferroptosis-related proteins and identified three ferroptosis-related proteins (CTSB, IDO1, and MDM4) with significant causal effects on PC risk. A proteome-wide scan further uncovered 13 proteins associated with PC. Two-step mediation MR supported a causal pathway from CLEC4G through the ferroptosis regulator CTSB to PC risk. In vitro, CLEC4G knockdown increased CTSB expression and ferroptosis activity, which suppressed PC cell proliferation, colony formation, migration, and invasion. Together, our genetic and experimental evidence indicates that CLEC4G promotes PC progression by limiting CTSB-associated ferroptotic activity in PC cells and supports further investigation of the CLEC4G-CTSB axis in PC.
Podoplanin Antibody SZ168 Alleviates Sepsis Inflammation and Macrophage Dysregulation via ERK Signaling.
Wang H, Heng J, Zhang Y … +6 more , Cui J, Li Y, Yu S, Gu X, Lu S, Zhao Y
Hum Mutat · 2026 · PMID 42272990 · Full text
BACKGROUND: Sepsis is a life-threatening condition marked by excessive inflammation and immune dysregulation. Macrophages are central to this process. Podoplanin (PDPN), a transmembrane glycoprotein, is upregulated in in...
BACKGROUND: Sepsis is a life-threatening condition marked by excessive inflammation and immune dysregulation. Macrophages are central to this process. Podoplanin (PDPN), a transmembrane glycoprotein, is upregulated in inflammatory macrophages, but its role in sepsis remains unclear. OBJECTIVE: The aim of this study is to investigate the role of PDPN and the therapeutic potential of its monoclonal antibody SZ168 in LPS-induced macrophages and to extend these observations with supplementary in vivo and preliminary clinical validation. METHODS: RAW264.7 macrophages were stimulated with LPS and treated with SZ168. PDPN expression and the effects of SZ168 on cytokine secretion, polarization, apoptosis, and ERK signaling were assessed by proteomics, qPCR, Western blotting, ELISA, and flow cytometry. siRNA-mediated PDPN knockdown was used to validate pathway dependence. During revision, additional Western blot validation of MEK, p90RSK, and c-Fos; supplementary in vivo experiments in a mouse sepsis model; and a preliminary clinical cohort analysis were incorporated to strengthen mechanistic and translational relevance. RESULTS: LPS stimulation significantly upregulated PDPN expression at both mRNA and protein levels in macrophages. SZ168 treatment reduced LPS-induced secretion of IL-6, TNF-, and IL-1; promoted anti-inflammatory polarization; and attenuated apoptosis. Revision-stage Western blot analyses further showed coordinated recovery of MEK, p90RSK, c-Fos, and p-ERK together with suppression of SERPINE1 after SZ168 treatment, especially in PDPN-knockdown cells. Supplementary in vivo experiments showed lower BUN, creatinine, inflammatory cytokines, and lung injury after SZ168 treatment. In a preliminary clinical cohort, serum PDPN levels were higher in patients with sepsis than in controls (23.81 ± 17.64 vs. 3.53 ± 0.58, < 0.001). CONCLUSION: The PDPN monoclonal antibody SZ168 attenuates inflammatory responses, promotes anti-inflammatory macrophage polarization, and inhibits apoptosis through modulation of the ERK signaling pathway in LPS-induced macrophages. The supplementary in vivo and preliminary human data added during revision further support the translational relevance of PDPN as a therapeutic target in sepsis.
TLR4 and RB1 as the Identified Lactate-Related Genes to Predict the Diagnostic Performance, Gene Regulatory Network, and Targeting Drugs in Depression.
Ding F, Chen J, Wu J … +1 more , Bian Q
Hum Mutat · 2026 · PMID 42253512 · Full text
BACKGROUND: Lactate is implicated in several brain diseases; however, its precise role in depression remains to be further elucidated. The current study looks into the role of lactate-associated genes in depression, alon...
BACKGROUND: Lactate is implicated in several brain diseases; however, its precise role in depression remains to be further elucidated. The current study looks into the role of lactate-associated genes in depression, along with their diagnostic and therapeutic potential. METHODS: Genes related to lactate were obtained from the Harmonizome database. Depression-related datasets were acquired from the GEO database, and differentially expressed genes (DEGs) were identified using the limma package. The overlapping genes from the DEGs and lactate-related genes were subjected to enrichment analyses using enrichR. The correlation analysis confirmed the validation of screened core genes via the random forest algorithm. Cytoscape was used for the construction of transcription factors and miRNA-based gene regulatory networks. Receiver operating characteristics (ROC) analysis was used to evaluate diagnostic performance. Molecular docking was performed to predict drug interactions. RESULTS: The lactate-related DEGs were seen to be implicated in processes like negative regulation of the apoptotic process and NOD-like receptor signaling pathways. TLR4 and RB1 were identified as core genes, showing elevated expression and strong diagnostic potential in depression. In addition to the positive correlation, TLR4 was shown to be the target of multiple miRNAs, while RB1 was unveiled to be the target of several transcription factors. Besides, the binding of RB1 (protein: 6C2R) to topotecan and dexamethasone was confirmed, while TLR4 (protein: 4R7N) could bind with Tlr4-IN-C34 and resatorvid. CONCLUSION: This study successfully identified TLR4 and RB1 as core lactate-related genes in depression, providing a new perspective on elucidating the role of lactate in the pathogenesis of depression.
A Novel Frameshift Variant Underlies Familial Phenotypic Heterogeneity in DFNA7.
Xu C, Nie Z, Wang S … +3 more , Zhu Y, Liu X, Guo Y
Hum Mutat · 2026 · PMID 42253511 · Full text
Pathogenic variants in the LIM-homeodomain transcription factor represent a rare yet critical etiology for autosomal dominant nonsyndromic hearing loss 7 (DFNA7) and less frequently, its autosomal recessive counterpart...
Pathogenic variants in the LIM-homeodomain transcription factor represent a rare yet critical etiology for autosomal dominant nonsyndromic hearing loss 7 (DFNA7) and less frequently, its autosomal recessive counterpart (ARNSHL). Here, we describe a novel heterozygous frameshift variant, c.405delT (p.Phe135LeufsTer3), identified in a three-generation Chinese family, cosegregating with progressive and asymmetric sensorineural hearing loss (ASNHL). Clinical manifestations exhibited significant intrafamilial phenotypic variability, with hearing loss (HL) severity ranging from mild to profound, and onset varying from infancy to mid-adulthood. High-resolution imaging revealed bilateral cochlear aperture stenosis (CAS) in the severely affected proband. Whole-exome sequencing (WES) and cosegregation analysis confirmed this novel variant. Structural modeling predicted the truncation of both the DNA-binding homeodomain and the C-terminus. Subsequent reporter assays demonstrated a significant loss of transcriptional activity. Furthermore, plasmid titration experiments and Actinomycin D chase assays functionally corroborated the haploinsufficiency mechanism and excluded the dominant-negative effect. Integrative multiomics profiling (RNA-seq and DIA-based proteomics) of in vitro HEI-OC1 model revealed molecular perturbations following deficiency, primarily involved in synaptic signaling and immune-inflammatory cascades. This study broadens the mutational landscape, refines the clinical phenotypic spectrum of DFNA7 and establishes insufficient dosage as the primary disease driver.
Integrative Multiomics Analysis Identifies a Novel Gene Signature That Predicts Chemotherapy Resistance and Poor Survival in Osteosarcoma.
Yang X, Lu X, Gao Z … +12 more , Lv W, Shen S, Liu S, Li Z, Liu R, Wang X, Shen Y, Yu D, Jin X, Wang H, Tang J, Tang Z
Hum Mutat · 2026 · PMID 42253510 · Full text
Chemotherapy resistance is the primary barrier to improving survival in osteosarcoma (OS), yet reliable predictive biomarkers remain limited. Here, we developed and validated a 13-gene signature via weighted gene coexpre...
Chemotherapy resistance is the primary barrier to improving survival in osteosarcoma (OS), yet reliable predictive biomarkers remain limited. Here, we developed and validated a 13-gene signature via weighted gene coexpression network analysis (WGCNA) of chemotherapy-resistant and sensitive OS transcriptomes. The risk model demonstrated robust prognostic value across four independent cohorts (TARGET-OS, GSE21257, GSE16091, and GSE39055). Multiscale analysis revealed that high-risk tumors exhibit proliferative hyperactivation, genomic instability with elevated TMB, and a paradoxical immune-cold phenotype despite the high mutational load. Single-cell and spatial transcriptomics demonstrated that high-risk malignant cells display dedifferentiated, stem-like properties, preferentially localize to hypoxic necrotic peripheries, and engage in extensive tumor-stromal crosstalk. Drug sensitivity predictions confirmed resistance to first-line chemotherapy agents. Collectively, these findings establish a clinically actionable 13-gene biomarker and provide a mechanistic framework linking transcriptional profiles to chemoresistance biology, exposing novel therapeutic vulnerabilities in OS.
E2F4 Mediates Mitophagy to Inhibit Ferroptosis in Esophageal Cancer Cells by Activating GPR176.
Xu W, Su F, Xie L … +5 more , Ding T, Qi X, Chen P, Ye Z, Lin W
Hum Mutat · 2026 · PMID 42253509 · Full text
Esophageal cancer (EC) is driven by complex dysregulated molecular networks, and ferroptosis-an iron-dependent, non-apoptotic form of regulated cell death-has emerged as a critical modulator of tumorigenesis. However, th...
Esophageal cancer (EC) is driven by complex dysregulated molecular networks, and ferroptosis-an iron-dependent, non-apoptotic form of regulated cell death-has emerged as a critical modulator of tumorigenesis. However, the functional contribution and mechanistic basis of GPR176 in ferroptosis regulation during EC progression remain largely unexplored. Here, we integrated computational and experimental approaches to delineate the role of GPR176 and its upstream regulator E2F4 in EC ferroptosis. Bioinformatic analysis revealed consistent upregulation of both GPR176 and E2F4 in EC tissues, which was further confirmed by molecular validation. Functional assays demonstrated that GPR176 overexpression conferred resistance to ferroptosis in EC cells, as reflected by reduced malondialdehyde, intracellular Fe, and lipid reactive oxygen species (ROS) accumulation, alongside altered expression of core ferroptosis mediators. This protective effect was associated with the suppression of mitophagy, as indicated by alterations in mitochondrial function and autophagy-related markers. Mechanistically, we demonstrated that E2F4 directly binds to the GPR176 promoter and transcriptionally activates its expression. Rescue experiments further validated that GPR176 overexpression abrogated the enhanced mitophagy and ferroptosis induced by E2F4 depletion. Collectively, our findings define an E2F4/GPR176/mitophagy axis that acts to suppress ferroptosis in EC, highlighting this pathway as a novel therapeutic target for inducing ferroptosis in EC intervention.
Study on the Mechanism of Hearing Loss Induced by USH2A Gene Knockout.
Chen C, Xu B, Dang J … +4 more , Tan H, Bian P, Wang Y, Guo Y
Hum Mutat · 2026 · PMID 42253508 · Full text
BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing loss, retinitis pigmentosa, and variable vestibular dysfunction. USH2A is one of the causative genes of USH. This study is aime...
BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing loss, retinitis pigmentosa, and variable vestibular dysfunction. USH2A is one of the causative genes of USH. This study is aimed at exploring the mechanism of hearing loss induced by USH2A gene knockout. METHOD: USH2A knockout (Ush2a) mice were used, and auditory brainstem response testing was performed on WT, Ush2a, and Ush2a mice. Then, the cochlea tissues were used to carry out immunofluorescence staining, hematoxylin and eosin (H&E) staining, and scanning electron microscopy (SEM). The mRNA expressions were detected by RT-qPCR. Finally, the differentially expressed genes (DEGs) in cochlear tissues of Ush2a and WT mice were identified by transcriptome sequencing. RESULTS: Compared to WT mice, Ush2a and Ush2a mice exhibited moderate-to-severe nonprogressive hearing loss, with more pronounced deficits at low (4 kHz) and high (32/24 kHz) frequencies. HE staining and immunofluorescence staining showed that the modiolus, stria vascularis, basilar membrane, and the number of inner hair cells and outer hair cells (OHCs) in USH2A knockout mice have not changed. However, SEM results showed that severe stereociliary collapse was evident in OHCs of the Ush2a group. In addition, through transcriptomic analysis, 3632 upregulated genes and 2921 downregulated genes were obtained in the Ush2a mice. Among these DEGs, the most DEGs associated with hearing loss were Scn2a, Shank2, Bsn, Fcer1g, Prkce, Tgfb1, and Irf7. CONCLUSION: This study demonstrates that USH2A deficiency disrupts auditory function through stereociliary instability and dysregulation of genes critical for synaptic transmission and cytoskeletal dynamics.
Novel African American Colorectal Cancer Variants Associate With Major Genomic Instability.
Rashid M, Brim H, Teng S … +8 more , Sobitan A, Cruz-Cosme R, Qiyi T, Koi M, Casazza K, Surtees JA, Carethers JM, Ashktorab H
Hum Mutat · 2026 · PMID 42253507 · Full text
UNLABELLED: Pathogenic variants of can increase mutational load within colorectal cells, which may drive initiation and progression of colorectal cancer (CRC). We identified several variants within among CRCs from Afri...
UNLABELLED: Pathogenic variants of can increase mutational load within colorectal cells, which may drive initiation and progression of colorectal cancer (CRC). We identified several variants within among CRCs from African Americans (AA). To predict and assess the functional significance of these variants, we employed a combination of in silico analyses and in vitro functionality assays. Our objective was to elucidate the correlation between computational predictions and functional outcomes. METHODS: A CRISPR-Cas9 knock-in approach was used to introduce and generate specific point mutations in Exons 21, 22, and 23 of in the wild-type (WT) CRC cell line SW620, which was confirmed with Sanger sequencing. We employed cell proliferation, microsatellite instability assays, and whole genome sequencing to assess biological and genetic consequences. We utilized immunofluorescence, Western blot, and coimmunoprecipitation methods to assess subcellular localization and differences in heterodimer MSH2 binding between WT and variant MSH3 proteins. RESULTS: We previously identified six novel, potentially pathogenic nonsynonymous variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, and c.G3241A) within six exons (Exons 8 (E413K), 9 (S466N), 20 (S920F), 21 (E976K), 22 (H1010Y), and 23 (E1081K), respectively) of among AA CRCs as assessed by computational bioinformatic and molecular dynamic simulation analysis. We successfully knocked in three of the MSH3 variants (Exons 21, 22, and 23). Biological phenotypic assays revealed no observable changes in cell morphology or proliferation between WT and -variant knocked-in cells, and no differences were observed in microsatellite assays. Subcellular localization of variant MSH3 protein was unaffected compared with WT, whereas the interaction between MSH3 and MSH2 was not impacted. Short tandem repeats (STRs), or microsatellites, are short DNA motifs of two to six base pairs repeated consecutively, and they serve as powerful genetic markers for studying inheritance patterns and disease-associated repeat instability. In our analysis, STR profiling revealed both repeat expansions and contractions across multiple motifs, with tetranucleotide repeats showing the most pronounced alterations. Notably, loci flanking (ATTT), (AGAT), and (CTTT/GTTT) displayed consistent repeat expansions (+1.5 to +2), whereas intronic regions within , , and exhibited contractions. Trinucleotide STRs revealed a mix of instability, with repeat gains at and losses near and . Pentanucleotide and hexanucleotide motifs were more stable overall, but expansions were still noted at , , and , and contractions at and . These findings highlight the bidirectional and motif-specific nature of STR instability driven by deficiency. Our results support the utility of STR-based assays as sensitive tools to detect nonclassical MSI events and deepen our understanding of 's role in preserving microsatellite integrity across the genome. CONCLUSION: This study investigated the functional consequences of MSH3 variants identified among AA CRCs. While CRISPR-Cas9 knock-in of MSH3 variants (Exons 21, 22, and 23) in SW620 cells did not alter cell morphology, proliferation, protein localization, or MSH2 binding, we observed genetic changes that collectively underscore the bidirectional nature of STR instability in -deficient cells and reinforce this protein's pivotal role in suppressing slippage at longer repeat motifs. This study advances our understanding of how deficiency contributes to genomic instability beyond canonically defined MSI loci, offering novel insights into the mutational landscapes of MMR-deficient tumors and how these mutations can potentially contribute to the outcome of AA CRC patients.
Mutation Spectrum of Hemoglobinopathies in Tunisia.
Moumni I, Khalfaoui K, Chebbi M … +8 more , Chaouch L, Ouragini H, Chaouechi D, Mellouli F, Ouederni M, Benkhaled M, Abbes S, Menif S
Hum Mutat · 2026 · PMID 42253506 · Full text
INTRODUCTION: Hemoglobinopathies are the most prevalent recessive disorders worldwide, characterized by wide molecular and clinical heterogeneity. They result from mutations within the alpha-, beta-, or delta-globin gene...
INTRODUCTION: Hemoglobinopathies are the most prevalent recessive disorders worldwide, characterized by wide molecular and clinical heterogeneity. They result from mutations within the alpha-, beta-, or delta-globin gene leading to aberrant expression or protein function. These abnormalities are widely spread throughout the Mediterranean basin. Due to their severity and disabling nature, hemoglobinopathies represent a major public health problem. Mutational screening of abnormal hemoglobins (Hbs) allows the creation of a mutation map, which forms the basis for a potential national prevention program in Tunisia. METHODS: A total of 260 Tunisian subjects were investigated using biochemical and molecular analyses to identify defects in the globin genes (HBA, HBB, and HBD). The study is aimed at determining the molecular spectrum of hemoglobinopathies and contributing to the development of a comprehensive Hb mutation map in Tunisia. RESULTS: Twenty-one -thalassemia mutations and 16 rare Hb variants were reported, affecting the HBA, HBD, and HBB genes. Rare Hb variants were identified and described for the first time among Tunisian patients, including Hb A-Babinga (HBD:c.410G>A; delta 136: Gly → Asp, GGT → GAT). Other variants, such as Hb Knossos, Hb Summer Hill, Hb Hope, and Hb Köln, which are uncommon in the Mediterranean region, were also detected. CONCLUSION: This study provides an updated overview of -thalassemia mutations and rare Hb variants in the Tunisian population. These findings are essential for understanding genetic and clinical diversity, improving the clinical management of hemoglobinopathies, and enhancing public health initiatives.
Toward Precision Acupuncture for Pain: Host Genetic Variability, Omics Biomarkers, and Treatment-Response Stratification.
Chang L, Pan Y, He X … +5 more , Yang J, Xiao L, Zhang J, He S, Xie Y
Hum Mutat · 2026 · PMID 42253505 · Full text
Pain is a heterogeneous clinical condition characterized by substantial interindividual variability in symptom severity and treatment response. Acupuncture has been widely used for the management of various pain disorder...
Pain is a heterogeneous clinical condition characterized by substantial interindividual variability in symptom severity and treatment response. Acupuncture has been widely used for the management of various pain disorders, including chronic musculoskeletal pain, migraine, and cancer-related pain. However, clinical outcomes remain highly variable across patients, suggesting that average treatment effects may not fully capture biologically and clinically meaningful response heterogeneity. Recent advances in human genetics and multiomics technologies have provided new opportunities to investigate the biological factors that may contribute to this variability. Current genetic evidence, derived mainly from candidate-gene studies, suggests that polymorphisms involved in pain perception and neuromodulatory pathways, including COMT and OPRM1, may influence individual sensitivity to acupuncture analgesia; however, these findings remain exploratory and require validation in larger and more diverse cohorts. In parallel, transcriptomic, epigenetic, proteomic, metabolomic, and inflammatory profiling studies have identified molecular changes associated with acupuncture treatment. These treatment-associated signals should be distinguished from predictive biomarkers: Baseline genetic or molecular features may help estimate the likelihood of response, whereas posttreatment molecular alterations more often reflect treatment engagement, biological adaptation, or downstream mechanistic effects. Although the available evidence remains fragmented and is often limited by small sample sizes, heterogeneous acupuncture protocols, variable analytical pipelines, and insufficient external validation, it provides a useful foundation for developing biomarker-informed approaches to acupuncture research. In this review, we summarize current evidence linking host genetic variability and omics-derived molecular signatures to acupuncture analgesia, clarify the conceptual distinction between predictive and treatment-associated biomarkers, and discuss the potential and limitations of response-stratified acupuncture. We further highlight key priorities for the field, including standardized treatment protocols, multicenter cohorts, prospective biospecimen collection, reproducible omics workflows, and external validation of prediction models. Together, these considerations support precision acupuncture as an emerging research framework for understanding and eventually improving individualized pain management, rather than as a currently established clinical strategy.
Haplotype Construction Using Embryos as Probands of the Pathogenic Variations in EXT1, CUL3, and HBA.
Shu D, Liu Y, Wang X … +2 more , Liang T, Wu Z
Hum Mutat · 2026 · PMID 42253504 · Full text
Preimplantation genetic testing (PGT) represents a crucial strategy in the prevention of monogenic disorders, ensuring that only embryos free from these genetic conditions are implanted during assisted reproductive techn...
Preimplantation genetic testing (PGT) represents a crucial strategy in the prevention of monogenic disorders, ensuring that only embryos free from these genetic conditions are implanted during assisted reproductive technologies. By analyzing the type of haplotypes of the variation of the probands or the carriers, we can significantly enhance the diagnostic precision of PGT. We presented a clinical strategy that uses embryos as probands to construct haplotypes; this innovative approach has successfully delineated the haplotypes associated with pathogenic variations in key genes, such as HBA (encoding hemoglobin subunit alpha), EXT1 (involved in exostoses), and CUL3 (a gene related to various developmental disorders). Ten embryos in three families were tested, all are diagnosed whether with the deletion variations or not by haplotype construction, Sanger sequencing, or PCR. Importantly, we compared SNP results with haplotype analysis by pedigree linkage or long reading sequence. This method can be considered when family members are incomplete and haplotype construction is otherwise unfeasible other than long reading sequencing.
YIF1B Mutational Dysregulation Drives Cutaneous Melanoma Progression by Remodeling the TME.
Wang X, Ding Y, Cai W … +2 more , Liu C, Shi H
Hum Mutat · 2026 · PMID 42253503 · Full text
YIF1B, a transmembrane protein involved in intracellular trafficking and signaling, is dysregulated in multiple cancers, but its role in SKCM remains unclear. We integrated multiomics data from cutaneous melanoma cohorts...
YIF1B, a transmembrane protein involved in intracellular trafficking and signaling, is dysregulated in multiple cancers, but its role in SKCM remains unclear. We integrated multiomics data from cutaneous melanoma cohorts, including gene expression, DNA methylation, and somatic mutation profiles. Using the similarity network fusion (SNF) algorithm, we performed molecular subtyping based on prognosis-associated epigenetic and mutational features. Finally, the biological role of YIF1B was validated in A-375 and A-875 melanoma cell lines using qRT-PCR, wound healing, and transwell migration/invasion assays following shRNA-mediated knockdown. Patients assigned to the worst-prognosis CS5 subtype exhibited poorer survival ( < 0.05), characterized by mutation and high YIF1B expression. Mechanistically, we showed that YIF1B impairs tumor-infiltrating CD8 T cell function. High YIF1B coupled with activation of the IL-6/JAK pathway produces a positive feedback loop in which tumor proliferation/metastasis is enhanced, as is T cell immunosuppression, eventually culminating in profound immunosuppression and tumor growth. Knockdown of YIF1B by shRNA reduced YIF1B levels in A-375 and A-875 cells, leading to suppression of cell motility and proliferation ( < 0.05). Whole-genome sequencing also revealed that activating alterations in IL-6/JAK pathway genes occur frequently in aggressive cutaneous melanoma and correlate with accelerated progression. We demonstrate that YIF1B drives cutaneous melanoma progression and enhances melanoma cell invasiveness. This function may be further enhanced in combination with activation of the IL-6/JAK pathway, suggesting an important interaction of signaling processes with immunological selection pressures. Together, YIF1B expression and IL-6/JAK pathway activation status are potential markers for SKCM prognostication and treatment guidance.
Distinct Pathogenic Mechanisms of Two Novel NHS Mutations Identified in Chinese Han Families With Nance-Horan Syndrome.
Li L, Song J, Qin M … +3 more , Zhou S, Liu J, Zheng G
Hum Mutat · 2026 · PMID 42253502 · Full text
Nance-Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by congenital cataracts, dental anomalies, and neurodevelopmental impairments, caused by mutations in the gene. In this study, two novel muta...
Nance-Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by congenital cataracts, dental anomalies, and neurodevelopmental impairments, caused by mutations in the gene. In this study, two novel mutations, c.3847C>T and c.2519_2520del, were identified in two unrelated Chinese Han families, and their pathogenic molecular mechanisms were elucidated. Functional analyses revealed that the c.3847C>T mutation exerts a dual pathogenic effect: It disrupts extracellular matrix homeostasis by downregulating and upregulating , and it triggers oxidative stress, evidenced by elevated ROS levels, altered BAX/BCL-2 ratio, and reduced expression, ultimately leading to apoptosis and impaired cell migration. In contrast, the c.2519_2520del mutation primarily impairs mitochondrial function, as indicated by decreased membrane potential, reduced ATP production, and downregulation of and . This mitochondrial dysfunction is further exacerbated by suppressed expression, contributing to metabolic disturbances, and by -mediated cell cycle arrest. These findings, for the first time, demonstrate that distinct types of mutations cause disease via divergent mechanisms, extracellular matrix disruption versus mitochondrial dysfunction, providing molecular insights into the clinical phenotypic heterogeneity of NHS and laying a theoretical foundation for the development of mutation-specific precision therapies.
Functional Interpretation of Recurrent Genetic Variants in Hepatocellular Carcinoma: Molecular Consequences and Clinical Relevance.
Ye Y, Xu Z, Wang J … +3 more , Chen C, Peng Y, Li B
Hum Mutat · 2026 · PMID 42253501 · Full text
Hepatocellular carcinoma (HCC) is characterized by substantial molecular heterogeneity shaped by recurrent genetic alterations. Large-scale genomic studies have defined the mutational landscape of HCC, but the biological...
Hepatocellular carcinoma (HCC) is characterized by substantial molecular heterogeneity shaped by recurrent genetic alterations. Large-scale genomic studies have defined the mutational landscape of HCC, but the biological interpretation and clinical utility of these variants remain incompletely established. Increasing evidence suggests that key driver alterations influence tumor behavior not only through direct pathway dysregulation but also through downstream transcriptional programs, epigenetic remodeling, proteomic changes, metabolic adaptation, and tumor-immune interactions. Therefore, variant interpretation in HCC requires a framework that extends beyond mutation frequency and integrates functional annotation, multiomics profiling, experimental validation, and clinical evidence. In this review, we summarize major recurrent genetic alterations in HCC, including variants affecting telomere maintenance, cell cycle control, WNT/-catenin signaling, and chromatin remodeling. We then discuss how these alterations shape molecular phenotypes across transcriptomic, proteomic, metabolic, and immune layers. Particular attention is given to distinguishing well-supported variant-phenotype relationships from emerging or exploratory associations. We further evaluate the translational relevance of recurrent variants in diagnosis, prognosis, liquid biopsy, and therapeutic stratification while emphasizing that most variant-informed applications in HCC remain investigational rather than clinically validated. Finally, we discuss current challenges and future directions, including functional genomics, single-cell and spatial profiling, and prospective clinical validation. This review proposes a variant-centered interpretive framework for understanding how recurrent genetic alterations contribute to HCC biology and how they may inform future precision oncology strategies.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe