Human molecular genetics最新文献

{"title":"PONG 2.0: allele imputation for the killer cell immunoglobulin-like receptors.","authors":"Suraju A Sadeeq, Laura A Leaton, Katherine M Kichula, Ticiana D J Farias, Neus Font-Porterias, Nicholas R Pollock, Christopher E Collora, Erick C Castelli, Christopher R Gignoux, Paul J Norman","doi":"10.1093/hmg/ddag075","DOIUrl":"https://doi.org/10.1093/hmg/ddag075","url":null,"abstract":"<p><p>Killer cell immunoglobulin-like receptors (KIRs) are polymorphic immune regulators that modulate natural killer and T cell responses via interactions with human leukocyte antigen (HLA) class I ligands. High combinatorial diversity of KIR and HLA influences infection, autoimmunity, cancer, transplantation, and reproductive success. Although comprehensive KIR genotyping is achievable through targeted sequencing, complex genomic architecture hampers large-scale disease studies using genome wide data. Here, we introduce PONG2.0, a computational framework that accurately imputes high-resolution genotypes for all KIR that interact with HLA, directly from SNP-array data. We trained multi-ancestry models using matched SNP and KIR alleles from a subset of the 1000 Genomes Project (EUR = 187, AMR = 93, SAS = 102, AFR = 102, EAS = 102), achieving 92-99% overall accuracy. Validation against targeted sequencing of 267 independent samples confirmed robust per-locus concordance (92.1-97.7%). Population-level benchmarking of > 8000 individuals showed strong agreement with targeted sequencing (R2 up to 0.999; median deviation 0.6-6.8%), demonstrating reliable genotyping of samples that were independent from the model-building data. PONG2.0 is implemented as an open-source R package with pre-trained models, providing an efficient and scalable solution for KIR immunogenetics in large-scale biobanks and cohort studies. https://github.com/NormanLabUCD/PONG2.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CoCoRV-nf: a powerful and cost-effective tool for rare variant analysis leveraging external biobank sequence data identified new candidate predisposition genes in amyotrophic lateral sclerosis and neuroblastoma.","authors":"Saima Sultana Tithi, Johnathan Cooper-Knock, Michael Benatar, Joanne Wuu, J Paul Taylor, Gang Wu, Wenan Chen","doi":"10.1093/hmg/ddag076","DOIUrl":"10.1093/hmg/ddag076","url":null,"abstract":"<p><p>Although sequencing costs have steadily decreased with advances in technology, they remain high for large scale studies. The design of traditional individual-disease sequencing studies is either case only or cases with relatively few controls, resulting in potential loss of statistical power for discovery of disease associated genes. Here we show that for a given number of sequenced cases, a large control sample size is critical to maximize power for rare variant burden analysis. Furthermore, we have developed an end-to-end workflow based tool (CoCoRV-nf) to facilitate the use of external biobank sequence resources as controls. The modules include consistent variant QC, variant annotation, ancestry population prediction, and gene based burden analysis using summary genotype information, and combined analysis from multiple independent results. The tool supports exomes and genomes from gnomAD and All of Us as controls with preprocessed datasets. We apply the tool in two rare neurological diseases: amyotrophic lateral sclerosis and neuroblastoma. For each disease, two case cohorts are paired with gnomAD and All of Us data, respectively, followed by a combined analysis. Not only did we recapture known genes, but also, we identified new candidate genes for both diseases. By leveraging multiple large external biobank sequence data, we demonstrate the feasibility of using our tool to maximize statistical power to identify new disease predisposition genes.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucolipidosis II: novel variants, clinical variation and assessment of HAP1 cells as a disease model.","authors":"Noura R Eissa, Ghada M Abdel-Salam, Marcelina Kretkiewicz, Eline Pieters, Jaak Jaeken, Gert Matthijs, Matthew P Wilson","doi":"10.1093/hmg/ddag068","DOIUrl":"https://doi.org/10.1093/hmg/ddag068","url":null,"abstract":"<p><p>Mucolipidosis type II is an autosomal recessive lysosomal storage disease resulting from biallelic variants in the GNPTAB gene encoding the N-acetylglucosamine phosphotransferase α/β subunits. Deficiency of this enzyme disrupts the mannose-6-phosphate (M6P) trafficking pathway, resulting in mistargeting of lysosomal acid hydrolases. Subsequently, lysosomal accumulation of undegraded macromolecules gives rise to a clinical phenotype with developmental/intellectual disability, skeletal deformities, coarse features, and cardiopulmonary dysfunction. Here, we report a cohort of eight patients (7 Egyptians and 1 Yemeni) from seven families with three reported homozygous pathogenic variants and three unreported variants (p.(Asn750Ilefs*4), p.(Val795Glyfs*7), and c.3602 + 2 T > C). In addition, the GNPTAB gene was ablated in the H. sapiens haploid HAP1 cells by CRISPR-Cas9 editing, to investigate the potential of this cell line for the assessment of variant pathogenicity. This included introduction of the recurrent c.3503_3504delTC variant. A phenotype of impaired autophagic flux was recapitulated, suggesting that HAP1 cells are a suitable model for this disorder.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish knockout models of atxn1a, atxn1b, and atxn1l reveal distinct and shared phenotypic and transcriptomic alterations.","authors":"Anwarul Karim, Pramuk Keerthisinghe, Sreeja Sarasamma, Nicholas A Ciaburri, Mabel Guerra Giraldez, Kylan Naidoo, James P Orengo","doi":"10.1093/hmg/ddag078","DOIUrl":"10.1093/hmg/ddag078","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 1 is a progressive neurodegenerative disorder caused by polyglutamine expansion in ATXN1, yet the normal physiological roles of ATXN1 and its paralog ATXN1L remain incompletely understood. To define these roles, we generated the first zebrafish knockouts (KOs) of the three ataxin-1 family genes, atxn1a, atxn1b, and atxn1l, using CRISPR/Cas9 and performed phenotypic and transcriptomic analyses. All KOs exhibited reduced early survival and mild larval growth deficits. Behavioral assays revealed both shared and paralog-specific effects: atxn1a mutants displayed a reproducible light-dependent locomotor deficit, whereas atxn1b and atxn1l mutants showed generalized hypoactivity. Adult behavioral assessment revealed a gradient of phenotypic severity, with atxn1a KOs displaying the earliest and most pronounced alterations in vertical tank exploration and the greatest impairment in swim-tunnel performance. RNA-seq at 5 days post-fertilization identified extensive transcriptional alterations, including both shared and gene-specific differentially expressed genes associated with neural differentiation, microglial/immune cell migration, and immune signaling. Co-expression network analysis further identified distinct KO-associated gene modules, including a phototransduction-enriched module strongly correlated with atxn1a KO status, providing a potential mechanistic link to its light-dependent locomotor phenotype. Together, these findings define conserved and specialized roles of ATXN1-family genes in locomotor behavior, neurodevelopment, retinal function, and immune-related processes.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppressive genetic interactions between haploinsufficient mitochondrial genes encoded in the 22q11.2 microdeletion locus define brain and cardiac phenotypes.","authors":"Meghan Wynne, Stephanie A Zlatic, Austin S Park, Amanda Crocker, Hadassah Mendez-Vazquez, Eliana Liporace, Avanti Gokhale, Cristy Tower-Gilchrist, Maxine Robinette, Ryan H Purcell, Gary J Bassell, Erica Werner, Jennifer Q Kwong, Victor Faundez","doi":"10.1093/hmg/ddag073","DOIUrl":"10.1093/hmg/ddag073","url":null,"abstract":"<p><p>Genomic copy number variations, such as the 22q11.2 microdeletion syndrome, cause pleiotropic disorders that affect diverse organ systems and disrupt neurodevelopment. Deletions of the 22q11.2 locus reduce the dosage of up to 46 protein coding genes, raising questions about the identity of haploinsufficient genes and their genetic interactions contributing to 22q11.2 phenotypes. Here, we dissect functional and molecular relationships between two genes encoded within the 22q11.2 locus: the mitochondrial ribosomal protein gene MRPL40 and the mitochondrial citrate transporter SLC25A1. We show that a MRPL40 null mutation disrupts mitochondrial translation, impairs respiration, and affects multiple components of the SLC25A1 interactome, including factors required for lipid metabolism, mitochondrial ribosome subunits, and the mitochondrial RNA processing machinery. In silico coessentiality network analysis revealed correlated and anticorrelated fitness interactions linking MRPL40 and SLC25A1 to mitochondrial translation, intermediate carbon metabolism, and interferon signaling. We determined that Mrpl40-null mutations are embryonic lethal in mice, but Mrpl40-/+ mice are viable and displayed embryonic cardiac development and adult behavioral phenotypes. Similarly, Slc25a1+/- animals showed embryonic cardiac developmental defects but lacked the adult behavioral phenotypes observed in Mrpl40-/+ mice. Surprisingly, transheterozygotic Slc25a1+/-;Mrpl40-/+ mice suppressed or mitigated cardiac development, behavioral, and brain transcriptome phenotypes observed in single heterozygotic animals. These results reveal that MRPL40 and SLC25A1 are haploinsufficient genes within the 22q11.2 locus that genetically and biochemically interact to define tissue development and physiology. Our findings provide a framework for understanding the complexity and type of gene dosage interactions within the 22q11.2 deletion syndrome locus.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts.","authors":"Paola Zanfardino, Alessandro Amati, Sharon Cox, Gennaro Agrimi, Stefano Doccini, Patricio Fernández-Silva, Apollonia Tullo, Jessica Rosati, Filippo M Santorelli, Vittoria Petruzzella","doi":"10.1093/hmg/ddag080","DOIUrl":"10.1093/hmg/ddag080","url":null,"abstract":"<p><p>Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an ultra-rare autosomal recessive neuropathy caused by mutations in the MTMR5/SBF1 gene. In this study, we characterized dermal fibroblasts derived from a patient carrying compound-heterozygous MTMR5/SBF1 variants (R763H/G1064E) and identified alterations affecting mitochondrial metabolism and cellular stress pathways. Patient fibroblasts exhibited fragmented mitochondrial networks with a shift toward fission, together with reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved. In line with our previous evidence of enhanced mitophagy, these findings support the presence of altered mitochondrial quality control. The reduction in cellular energy production was not accompanied by increased glycolytic activity, indicating a metabolically quiescent phenotype. Transcriptomic profiling revealed dysregulation of the PI3K/AKT signalling pathway. AKT phosphorylation at Ser473 was increased in the absence of complete canonical AKT activation. These signalling changes were associated with increased expression of p53 and p21 and with features consistent with premature cellular senescence. Overall, our findings identify metabolic quiescence and premature senescence as previously unrecognized aspects of CMT4B3 cellular pathology and suggest that altered coordination between mitochondrial metabolism and intracellular signalling may contribute to disease pathogenesis.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR/dCas9-mediated tuning of DMPK transcription reveals a quantitative relationship between toxic repeat RNA expression and MBNL1 activity in myotonic dystrophy.","authors":"Lise Ripken, Thomas D Hoekman, Marieke Willemse, Maeve L Troost, Angelique N Kenyon, Walther J A A van den Broek, Derick G Wansink","doi":"10.1093/hmg/ddag079","DOIUrl":"10.1093/hmg/ddag079","url":null,"abstract":"<p><p>Myotonic dystrophy type 1 (DM1) is caused by (CUG)n-expanded DMPK transcripts that sequester the splicing factor MBNL1 in the nucleus, resulting in widespread splicing abnormalities. Although significant progress has been made in understanding DM1 pathogenesis, the contribution of DMPK transcript levels to disease severity, and the variability of these levels across cell types, tissues, and patients, remains poorly understood. To investigate this in a quantitative manner, we developed isogenic human immortalized myoblast models with inducible modulation of DMPK RNA levels using CRISPR activation (CRISPRa) and interference (CRISPRi) guided by synthetic sgRNAs. CRISPRa elevated DMPK RNA levels by more than three-fold, intensifying MBNL1-dependent splicing defects. In contrast, CRISPRi reduced DMPK RNA expression by approximately 80%, partially rescuing splicing abnormalities. These changes were validated by visualizing (CUG)n foci using RNA FISH. Lowering DMPK transcript levels increased the availability of free nucleoplasmic MBNL1, whereas upregulation further depleted MBNL1, reinforcing the central role of MBNL1 sequestration in repeat RNA toxicity. Our findings demonstrate that expanded DMPK transcript levels modulate free MBNL1 concentration and alternative splicing in a dose-dependent manner, underscoring the central role of repeat RNA expression in DM1 pathogenesis. These models provide a powerful platform for dissecting variability in DMPK expression and for defining the therapeutic thresholds required for effective DMPK knockdown, thereby offering critical insights for the design and evaluation of DMPK and MBNL1-directed therapeutic strategies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the epigenetic code: future Frontiers in predictive biomarkers for intellectual disability in fragile X syndrome.","authors":"Hanan Ali Alatawi, Jayda G Eldiasty","doi":"10.1093/hmg/ddag081","DOIUrl":"https://doi.org/10.1093/hmg/ddag081","url":null,"abstract":"<p><p>Fragile X Syndrome (FXS) remains the leading inherited cause of intellectual disability (ID), yet the classic CGG repeat expansion on the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene often fails to provide a precise prognostic map for cognitive outcomes. While the expansion is the primary trigger, the resulting epigenetic landscape, characterized by DNA hypermethylation and chromatin remodelling, is the true driver of gene silencing and phenotypic severity. This review critically evaluates the shift from traditional genetic screening to advanced epigenetic profiling as a robust framework for predicting ID in FXS. We synthesize emerging evidence on how quantitative epigenetic signatures can bridge the gap between genotype and the heterogeneous cognitive phenotypes observed in clinical practice. We explore the architecture of FMR1 silencing, emphasizing the role of mosaicism and epigenetic heterogeneity in shaping neurodevelopmental trajectories. A significant focus is placed on cutting-edge technologies, including single-cell epigenomics and CRISPR/dCas9-mediated epigenetic editing, which are transforming our ability to quantify 'epigenetic load.' Furthermore, we discuss the integration of machine learning algorithms to analyze multi-omics data, offering a pathway toward personalized prognostic scoring. We also address the clinical transition of peripheral biomarkers (e.g. blood-based methylation assays) as surrogates for central nervous system pathology. The future of FXS management lies in 'precision prognosis.' By decoding the epigenetic markers that precede and accompany cognitive decline, clinicians can move toward earlier diagnosis and targeted interventions. This review outlines a strategic roadmap for standardizing epigenetic assays, highlighting their potential to revolutionize the predictive landscape of neurodevelopmental disorders.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-acetylcysteine suppresses retinal defects in Drosophila models of SNRNP200-associated retinitis pigmentosa.","authors":"Sara K Mayer, Quinton H Christensen, Hailey McCoy-Munger, Nathaniel P Mohar, Valentina Botero, Seth M Tomchik, Yikang Rong, Arlene V Drack, Lori L Wallrath","doi":"10.1093/hmg/ddag077","DOIUrl":"10.1093/hmg/ddag077","url":null,"abstract":"<p><p>Retinitis Pigmentosa (RP) is an inherited retinal degenerative disease that affects 1 in 4000 individuals worldwide and can lead to complete blindness. Early stages of RP involve death of rod photoreceptors via apoptosis, causing loss of peripheral and night vision, which is followed by death of cone photoreceptors, leading to loss of central and daytime vision. Mutations in over 300 genes cause RP. Many of these genes encode retina-specific proteins; however, some encode globally expressed proteins, such as pre-mRNA splicing factors. This study is focused on mutations in the SNRNP200 gene encoding a core pre-mRNA splicing factor. The pathological mechanisms of SNRNP200-associated RP are not well understood and treatments are limited. An approach to study pathogenic mechanisms is to utilize model organisms. Therefore, we developed Drosophila models in which RP-causing mutations were introduced into the Drosophila melanogaster orthologue Snrnp200. In addition, we used RNAi to knock-down Snrnp200 in the developing eye. Depletion of Snrnp200 caused an adult rough eye phenotype due to apoptosis of cells in the retina. When human RP-causing mutations were modeled in Drosophila Snrnp200, they resulted in abnormal retinal electrophysiology and defective patterning of photoreceptors. Further analysis of the photoreceptors revealed mitochondrial defects and altered expression of genes related to redox homeostasis. Consistent with these changes, treatment with the antioxidant N-acetylcysteine (NAC) partially suppressed the photoreceptor defects. Taken together, these findings established a new genetic model for studies of splicing-factor associated RP that recapitulates aspects of the human disease and suggests that antioxidants might serve as a treatment for individuals with SNRNP200-associated RP.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 17","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential regulatory relationship between hsa_circ_0000973 and MBOAT2 in hypertriglyceridemia with abnormal glucose metabolism.","authors":"Fengdan Wang, Yixue Yang, Xiaotong Li, Yang Xu, Shoumeng Yan, Bo Li, Di Zhao","doi":"10.1093/hmg/ddag074","DOIUrl":"https://doi.org/10.1093/hmg/ddag074","url":null,"abstract":"<p><p>Hypertriglyceridemia (HTG) frequently occurs in population with abnormal glucose metabolism (AGM), exacerbating risk. In our preliminary researches, we have screened hsa_circ_0000973 and MBOAT2 as the possible regulatory elements of HTG in AGM patients. This study enrolled 142 AGM subjects (71 with HTG, 71 with normal triglycerides) to investigate the role and mechanism of the hsa_circ_0000973 and MBOAT2 in AGM-associated HTG. Expression levels of hsa_circ_0000973 and MBOAT2 were measured by RT-qPCR. Diagnostic performance was evaluated via ROC analysis. Functional validation was performed in an insulin-resistant (IR) HepG2 cell model following knockdown of hsa_circ_0000973 or MBOAT2 using siRNA. Cellular triglyceride (TG) content, glucose uptake, proliferation, apoptosis, and expression of lipid metabolism transcription factors (SREBP-1c, PPARα, PPARγ) were assessed. In the AGM population, expression of both hsa_circ_0000973 and MBOAT2 was significantly downregulated in the HTG group and negatively correlated with serum TG levels (P <0 .01). hsa_circ_0000973 exhibited high diagnostic accuracy for HTG in the AGM population (AUC = 0.95). In HepG2-IR cells, knockdown of hsa_circ_0000973 decreased MBOAT2 expression, increased cellular TG accumulation and residual glucose, inhibited proliferation, and promoted apoptosis. Similar phenotypes were observed upon MBOAT2 knockdown. Both knockdowns upregulated SREBP-1c and downregulated PPARα and PPARγ. This study identified that hsa_circ_0000973 may serve as a candidate biomarker for identifying HTG specifically within the AGM population. Our in vitro experiments further suggested that, in the setting of AGM, hsa_circ_0000973 may jointly regulated TG metabolism alongside MBOAT2.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 16","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}