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Open AccessArticle

Clinical and Genetic Determinants of Hepatocellular Carcinoma in a Turkish Cohort: Impact of SLCO1B1 and SLCO1B3 Germline Variations and Demographic Risk Factors

by Zuhal Altintas

Int. J. Mol. Sci. 2026, 27(14), 6214; https://doi.org/10.3390/ijms27146214 - 12 Jul 2026

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Abstract

Organic anion-transporting polypeptides (OATPs) are crucial for hepatic uptake. However, the independent contribution of SLCO1B1/1B3 germline variations to hepatocellular carcinoma (HCC) susceptibility remains controversial. This study investigated SLCO1B1/1B3 polymorphisms and HCC risk in a Turkish cohort, accounting for clinical, viral, and metabolic confounders. [...] Read more.

Organic anion-transporting polypeptides (OATPs) are crucial for hepatic uptake. However, the independent contribution of SLCO1B1/1B3 germline variations to hepatocellular carcinoma (HCC) susceptibility remains controversial. This study investigated SLCO1B1/1B3 polymorphisms and HCC risk in a Turkish cohort, accounting for clinical, viral, and metabolic confounders. In this retrospective case–control study (81 HCC patients, 162 healthy controls), fully adjusted multivariable logistic regression models were constructed across multiple inheritance configurations (dominant, recessive, and additive) and adjusted for age, sex, and viral status (HBV/HCV) to address demographic and etiological discrepancies. Genotyping for SLCO1B1 (c.388A>G, c.521T>C) and SLCO1B3 (c.334T>G, c.699G>A) was performed using PCR-RFLP, cross-verified via automated digital capillary electrophoresis. Exploratory univariate analysis showed the SLCO1B1 388A>G variant was more prevalent in the HCC group. However, after strict adjustments for multiplicity and controlling for background viral etiology, age (OR: 1.10) and male sex (OR: 5.82, 95% CI: 2.74–12.41) remained the primary independent predictors, whereas the statistical significance of the genetic variant completely dissolved (p = 0.673). Notably, HCC patients exhibited profound hypocholesterolemia that significantly correlated with liver dysfunction severity; a significant inverse correlation was found between Child-Pugh scores and total cholesterol (r = −0.286, p = 0.031), validating that metabolic decline is a consequence of hepatic synthetic failure rather than an independent risk factor. Ultimately, age, male sex, and background etiological factors are the primary independent determinants characterizing HCC in this cohort, confirming that common germline SLCO variations do not exert a robust independent influence once major demographic and clinical confounders are considered. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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20 pages, 1320 KB

Open AccessArticle

Bayesian Population-Based Prevalence Estimation of KCNV2-Associated Retinopathy: A Comparative Analysis of Disease-Associated Variant Frequencies in Russian and Global Populations

by Anastasiia V. Rozhkova, Ekaterina A. Rutkovskaya, Vitaly V. Kadyshev, Anton A. Esibov, Almaqdad Alsalloum, Ekaterina S. Kuznetsova, Julia A. Krupinova, Olga N. Mityaeva, Kristina K. Shefer, Ernest V. Boiko, Olesya V. Sagaydak, Natalya A. Doroshchuk, Maria V. Makarova, Mary Woroncow, Viktor P. Bogdanov and Pavel Y. Volchkov

Int. J. Mol. Sci. 2026, 27(13), 5911; https://doi.org/10.3390/ijms27135911 - 30 Jun 2026

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Abstract

Cone dystrophy with supernormal rod responses (CDSRR) is a rare autosomal recessive hereditary retinal dystrophy caused by biallelic KCNV2 variants. Accurate prevalence data remain limited because current estimates rely on clinically ascertained cases. This study aimed to estimate its population prevalence by integrating [...] Read more.

Cone dystrophy with supernormal rod responses (CDSRR) is a rare autosomal recessive hereditary retinal dystrophy caused by biallelic KCNV2 variants. Accurate prevalence data remain limited because current estimates rely on clinically ascertained cases. This study aimed to estimate its population prevalence by integrating curated variant evidence and large-scale population genomics resources. The key methodological feature of this study is a multi-tiered pathogenicity framework combined with estimation of a biologically plausible prevalence range: Known pathogenic variants define conservative estimates, whereas probably pathogenic variants and strong variants of uncertain significance define broader estimates. Allele frequencies were analyzed in 807,162 individuals from the gnomAD database and 144,127 Russian genomes from GDB and EvogenDB. A Bayesian framework was applied to calculate disease prevalence from aggregated carrier frequencies across predefined variant tiers. Conservative estimates based on known pathogenic variants, were 1 in 343,926 globally and 1 in 1,911,347 in Russia. Including broader tiers increased estimates to 1 in 14,620 and 1 in 32,764, respectively. Compared to previous clinically ascertained prevalence of 1 in 865,000, these estimates define a wider biologically plausible prevalence range and are consistent with possible clinical underascertainment. This tier-based approach accounts for uncertainty in variant classification when estimating rare disease prevalence. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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24 pages, 3859 KB

Open AccessArticle

Whole-Genome Re-Sequencing Reveals Genetic Diversity and Population History of Arunachali Mithun (Bos frontalis)

by Kuluve Chotso, Hanumant S. Rathore, Harshit Kumar, Jayanta Kumar Chamuah, Sapunii S. Hanah and Girish Patil Shivanagowda

Int. J. Mol. Sci. 2026, 27(13), 5824; https://doi.org/10.3390/ijms27135824 - 27 Jun 2026

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Abstract

The Arunachali mithun (Bos frontalis) is a semi-domesticated bovine of profound cultural and economic significance to the indigenous Arunachali tribal communities of Northeastern India, yet it remains among the least genomically characterised large ruminants, leaving its conservation status without an empirical [...] Read more.

The Arunachali mithun (Bos frontalis) is a semi-domesticated bovine of profound cultural and economic significance to the indigenous Arunachali tribal communities of Northeastern India, yet it remains among the least genomically characterised large ruminants, leaving its conservation status without an empirical genetic foundation. We performed whole-genome re-sequencing (~10× coverage) of 11 individuals and analysed 4,943,593 high-quality biallelic single nucleotide polymorphisms (SNPs) after stringent quality control. Genome-wide mean observed heterozygosity (H_o = 0.2854), expected heterozygosity (H_e = 0.3347), and nucleotide diversity (π = 7.16 × 10⁻⁴) revealed moderate genetic diversity, substantially lower than that of related commercial bovine species. A consistent heterozygosity deficit (H_o − H_e = −0.0493) and the convergence of four independent inbreeding coefficients around 0.143–0.147 indicated moderate inbreeding of predominantly reflecting an ancient origin, corroborated by runs of homozygosity (ROH) analysis in which 93.2% of 24,937 detected segments fell in the short length class (100–250 kb). Linkage disequilibrium decayed from r² ≈ 0.57 at <100 kb to a plateau of r² ≈ 0.33 beyond 4–5 Mb, consistent with a small effective population size (N_e) declining from approximately 101,850 (~2228 generations ago) to approximately 160 (~5 generations ago), with ab Ne of approximately 3865 at ~100 generations ago and 423 at ~10 generations ago. These findings establish a whole-genome-based genetic diversity baseline for the Arunachali mithun and provide actionable genomic evidence for conservation and managed breeding interventions. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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12 pages, 1597 KB

Open AccessArticle

DNA-Mimic Antirestriction Proteins ArdA Could Regulate Gene Expression in Escherichia coli

by Anna A. Utkina, Anna A. Kudryavtseva, Rodion V. Berezov, Kamilla V. Mekhantseva, Olga E. Melkina, Sergey M. Rastorguev, Mikhail A. Skutel, Artem B. Isaev and Ilya V. Manukhov

Int. J. Mol. Sci. 2026, 27(12), 5595; https://doi.org/10.3390/ijms27125595 - 20 Jun 2026

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Abstract

Antirestriction proteins protect mobile genetic elements from the host’s restriction-modification systems. Here, we investigated the ability of ArdA and ArdB antirestriction proteins to regulate gene expression in an engineered E. coli K-12 MG1655-based biosensor strain. This biosensor strain harbors a lux-based reporter [...] Read more.

Antirestriction proteins protect mobile genetic elements from the host’s restriction-modification systems. Here, we investigated the ability of ArdA and ArdB antirestriction proteins to regulate gene expression in an engineered E. coli K-12 MG1655-based biosensor strain. This biosensor strain harbors a lux-based reporter system controlled by the AllR-repressed promoter. Although structurally similar, DNA-mimic ArdA proteins interact with AllR differently. Recently described small sArdC and well-known ArdA from the conjugative plasmid R64 appear to bind AllR and open the promoter, while the other tested antirestriction proteins (small sArdN protein and various full-sized ArdA proteins from different sources) have no effect on gene expression under AllR-controlled promoter. Direct binding between ArdA and AllR was experimentally confirmed using pull-down assays with His-tagged ArdA. Our study opens up prospects for the specific use of antirestriction proteins for the regulation of gene expression. Surprisingly, ArdB, a non-DNA-mimic antirestriction protein used initially as a control, was also able to open the promoter, apparently through nonspecific interaction with DNA. We verified this effect with a distant ArdB homolog from a rhizobacterium, which was also able to open the promoter. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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35 pages, 11474 KB

Open AccessArticle

A Novel Lytic Podovirus AP-20-A Infecting Sinorhizobium meliloti: Mosaic Genome with Cross-Phylum Homology and Implications for Inoculant Establishment

by Alexandra P. Kozlova, Marina L. Roumiantseva, Alla S. Saksaganskaia, Maria E. Vladimirova, Victoria S. Muntyan, Maria K. Gorbunova and Andrey N. Gorshkov

Int. J. Mol. Sci. 2026, 27(12), 5515; https://doi.org/10.3390/ijms27125515 - 18 Jun 2026

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Abstract

This study characterizes AP-20-A, a lytic podovirus infecting Sinorhizobium meliloti, isolated from agricultural chernozem. Its 49.4 kbp genome shows negligible intergenomic similarity with known rhizobiophages (<2%). Core structural proteins—the major capsid protein (MCP) and terminase large subunit (TerL)—show closest homology to podoviruses [...] Read more.

This study characterizes AP-20-A, a lytic podovirus infecting Sinorhizobium meliloti, isolated from agricultural chernozem. Its 49.4 kbp genome shows negligible intergenomic similarity with known rhizobiophages (<2%). Core structural proteins—the major capsid protein (MCP) and terminase large subunit (TerL)—show closest homology to podoviruses infecting Paenibacillus, rather than to alphaproteobacterial viruses, suggesting cross-phylum horizontal gene transfer. This exchange is ecologically plausible, as Paenibacillus and Sinorhizobium co-exist in the rhizosphere. Over 63% of predicted proteins are functionally uncharacterized, with structural homologs detected in bacteria, archaea, and eukaryotes. We report the first identification in a rhizobiophage of a Tad2-like domain, predicted to block the bacterial Thoeris type II anti-phage defense. AP-20-A infected 56% of native S. meliloti strains; agrocenose isolates showed higher resistance than phytocenose isolates, evidence of local co-evolution. Among susceptible strains, 60% entered putative pseudolysogeny (with one strain exhibiting growth stimulation), whereas a symbiotically elite inoculant strain was completely lysed within hours. Some host strains carry additional AbiE systems; whether these independent defense–counterdefense layers interact during infection remains unknown. We conclude that resident phages represent a selective force that can disrupt inoculant establishment, underscoring the need to integrate soil virome assessment into agricultural microbiome management. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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25 pages, 2271 KB

Open AccessArticle

Neuronal Injury and Regeneration-Linked Gene Expression Dynamics in the Hypothalamic–Pituitary–Adrenal Axis Following Experimental Traumatic Brain Injury

by Halil Ulutabanca, Serhat Albayrak, Zeynep Yilmaz Şükranli, Begüm Er, Eray Abat and Serpil Taheri

Int. J. Mol. Sci. 2026, 27(12), 5172; https://doi.org/10.3390/ijms27125172 - 7 Jun 2026

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Abstract

Traumatic brain injury (TBI) induces complex molecular and neuroendocrine alterations that extend beyond the site of injury. The hypothalamic–pituitary–adrenal (HPA) axis, a hierarchically organized neuroendocrine system composed of the hypothalamus, pituitary gland, and adrenal glands, plays a central role in coordinating stress and [...] Read more.

Traumatic brain injury (TBI) induces complex molecular and neuroendocrine alterations that extend beyond the site of injury. The hypothalamic–pituitary–adrenal (HPA) axis, a hierarchically organized neuroendocrine system composed of the hypothalamus, pituitary gland, and adrenal glands, plays a central role in coordinating stress and metabolic homeostasis. Despite its critical importance, the temporal transcriptional mechanisms underlying HPA axis dysregulation following TBI remain poorly understood, particularly in relation to coordinated neuronal injury and regeneration processes. This study aimed to investigate the time-dependent transcriptional dynamics of genes associated with neuronal injury and regeneration within the HPA axis following experimental TBI. Moderate-to-severe TBI was induced in Sprague–Dawley rats using a controlled cortical impact (CCI) model. Animals were allocated into sham, acute (24 h), and chronic (30 days) groups. Transcript profiles of 24 HPA axis- and neuroregeneration-related genes were analyzed in hypothalamic, pituitary, and adrenal tissues using quantitative real-time PCR, with normalization to a housekeeping gene and statistical evaluation of differential expression across time points. TBI induced distinct, tissue-specific, and time-dependent transcriptional alterations across the HPA axis. In the acute phase, stress-response genes showed divergent regulation between central and peripheral tissues, whereas the chronic phase was characterized by transcriptional reorganization involving neurotrophic, metabolic, and neuroendocrine pathways. Key regulators such as Hif1a, Rad18, Avp, Gata3, and OxtR exhibited significant and region-specific expression changes. These findings demonstrate that TBI triggers coordinated yet heterogeneous transcriptional responses within the HPA axis, linking central injury to systemic endocrine adaptation. This study provides novel insight into the molecular basis of neuroendocrine dysfunction and recovery after TBI and identifies candidate targets for future therapeutic strategies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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14 pages, 4563 KB

Open AccessArticle

Fecal Cloacibacillus porcorum Improves Non-Invasive Diagnosis of Colorectal Adenoma in the Hong Kong Population

by Yao Zeng, Effie Yin Tung Lau, Silin Ye, Jiawei Lu, Rui Zhang, Ruoyu Hu and Jessie Qiaoyi Liang

Int. J. Mol. Sci. 2026, 27(10), 4457; https://doi.org/10.3390/ijms27104457 - 15 May 2026

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Abstract

We previously developed a four-marker panel for the diagnosis of colorectal cancer (CRC) and adenoma. This study aimed to identify novel bacterial markers to improve adenoma detection using metagenomics and qPCR. Candidate markers were identified from metagenomic data (n = 492) using [...] Read more.

We previously developed a four-marker panel for the diagnosis of colorectal cancer (CRC) and adenoma. This study aimed to identify novel bacterial markers to improve adenoma detection using metagenomics and qPCR. Candidate markers were identified from metagenomic data (n = 492) using ANCOM-BC2 and Spearman’s rank correlation analysis and were subsequently validated in an independent cohort (n = 426). Diagnostic performance was assessed both individually and in combination with our previously identified markers and FIT. Metagenomic analysis identified 21 candidate markers that increased along the normal–adenoma–carcinoma axis. Two top candidates, Cloacibacillus porcorum (Cp) and Intestinimonas butyriciproducens, were validated via qPCR and showed significant correlations with metagenomic abundances (both p < 0.0001). ROC analysis demonstrated that Cp levels significantly distinguished CRC and adenoma from controls, whereas I. butyriciproducens distinguished only CRC. The prevalence of Cp was significantly higher in adenoma and CRC than in controls (all p < 0.05). Multivariate analysis confirmed that Cp was independently associated with CRC and adenoma diagnoses. Adding Cp to the four-marker panel improved diagnostic sensitivity from 44.8% to 58.7% for adenoma and from 85.7% to 88.6% for CRC (specificity = 85%). When further combined with FIT, Cp improved sensitivity from 47.6% to 64.3% for adenoma and from 95.2% to 96.2% for CRC (specificity = 84.6%). C. porcorum is a novel bacterial marker that may aid in the non-invasive diagnosis of colorectal adenoma. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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14 pages, 578 KB

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Insights into Copy Number Variation Architecture in Black Bengal Goat Genome

by Sonali Sonejita Nayak, Shikha Mittal and Manjit Panigrahi

Int. J. Mol. Sci. 2026, 27(9), 4045; https://doi.org/10.3390/ijms27094045 - 30 Apr 2026

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Abstract

Copy number variations (CNVs) are a major source of structural genomic diversity that influences adaptation, reproduction, and production traits in livestock. The Black Bengal goat, an economically important Indian breed known for its high fecundity, superior skin quality, and resilience to humid tropical [...] Read more.

Copy number variations (CNVs) are a major source of structural genomic diversity that influences adaptation, reproduction, and production traits in livestock. The Black Bengal goat, an economically important Indian breed known for its high fecundity, superior skin quality, and resilience to humid tropical climates, was studied to uncover its structural genomic landscape. We performed whole-genome CNV analysis using high-depth (10×) sequencing data from eight individuals. A total of 31,816 copy number variants (CNVs) were identified, predominantly duplications, with an average length of approximately 45 kb. These CNVs were combined into 8910 copy number variation regions (CNVRs) covering approximately 0.15 Gb (about 5.3% of the autosomal genome). CNVR hotspots were mainly located on chromosome 1. Gene annotation showed that regions overlapping with CNVs and CNVRs contained more than 1987 protein-coding genes involved in pathways related to immunity, reproduction, metabolism, and extracellular matrix (ECM) organization. The presence of CNVs involving genes such as GDF9 and BMPR1B on chromosomes 7 & 6, respectively, is important because it indicates that the breed has a high reproductive capacity due to dosage-sensitive duplications. Changes in the extracellular matrix and increased dermal strength have been linked to duplications of genes such as COL6A1, LAMC2, LAMB3, FMN1, and CLDN1. This helps explain the superior hide quality of the breed. This research offers a comprehensive map of CNVs and CNVRs within the genome of the Black Bengal goat. It demonstrates how these duplications lead to structural changes that enhance both reproductive performance and skin resilience. These findings provide a valuable genomic resource for future marker-assisted selection, comparative genomics, and conservation breeding programs aimed at preserving indigenous goat populations. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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12 pages, 1414 KB

Open AccessArticle

Overexpression of FGFR2 in Mandibular Ameloblastoma Is Potentially Associated with Gene Amplification and Deletion

by Nattanit Boonsong, Nakarin Kitkumthorn, Puangwan Lapthanasupkul, Kittipong Laosuwan, Wacharaporn Thosaporn, Jutamad Makyoo and Anak Iamaroon

Int. J. Mol. Sci. 2026, 27(8), 3443; https://doi.org/10.3390/ijms27083443 - 12 Apr 2026

Cited by 1 | Viewed by 866

Abstract

Ameloblastoma (AM) is a common locally invasive benign odontogenic tumor in Asian populations. Although fibroblast growth factor receptor 2 (FGFR2) mutations have been reported in AM, FGFR2 amplification, the predominant form of FGFR2 aberration in human cancers, remains unexplored. This study [...] Read more.

Ameloblastoma (AM) is a common locally invasive benign odontogenic tumor in Asian populations. Although fibroblast growth factor receptor 2 (FGFR2) mutations have been reported in AM, FGFR2 amplification, the predominant form of FGFR2 aberration in human cancers, remains unexplored. This study aimed to evaluate FGFR2 protein expression, FGFR2 gene copy number variations, and their associations with demographic and clinico-radio-pathological parameters in mandibular AM. Eighty-seven cases of mandibular AM and 10 dental follicle (DF) specimens were included. FGFR2 protein expression was assessed by immunohistochemistry, and gene copy number variations were analyzed using the quantitative real-time polymerase chain reaction (qPCR) technique. Clinical data, including age, gender, tumor size, radiographic features, histological subtype, and recurrence history, were examined for associations with FGFR2 alterations. FGFR2 protein overexpression was observed in 95.4% of AM cases and was not significantly associated with demographic or clinico-radio-pathological variables. FGFR2 gene amplification was detected in 52.5% of cases, while 8.2% showed gene deletion. Notably, 50.8% of cases exhibited concurrent FGFR2 amplification and overexpression, and all cases with FGFR2 gene deletion also demonstrated FGFR2 overexpression. These findings suggest that FGFR2 gene amplification and deletion may contribute to FGFR2 overexpression and play a significant role in the molecular pathogenesis of mandibular AM. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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19 pages, 1973 KB

Open AccessArticle

A Whole-Exome Sequencing-Based Exploration of Chronic Kidney Disease of Unknown Etiology (CKDu) in an Endemic Population in Sri Lanka

by Wesley Tom, Chiran Weerakoon, Nirmalee Fernando, Isuru Hasantha, Manoj Bandara, Gary Krzyzanowski, Shanika Nanayakkara, Dominic Cosgrove, Nishantha Nanayakkara and M. Rohan Fernando

Int. J. Mol. Sci. 2026, 27(8), 3369; https://doi.org/10.3390/ijms27083369 - 9 Apr 2026

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Abstract

A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30–60 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension [...] Read more.

A distinct form of chronic kidney disease of unknown etiology (CKDu) has emerged in tropical regions of Sri Lanka, predominantly affecting individuals aged 30–60 years in the North Central Province. Unlike conventional chronic kidney disease (CKD), CKDu occurs independently of diabetes or hypertension and is characterized by tubulointerstitial damage, including tubular atrophy, interstitial inflammation, and fibrosis. Epidemiological studies showed familial clustering, suggesting an underlying genetic predisposition. This study aimed to identify genetic variants associated with CKDu in Sri Lankan populations using whole-exome sequencing (WES). Eighty-six individuals (47 CKDu patients and 39 controls) were recruited from endemic and non-endemic regions. Physiological, biochemical, and geographic parameters were recorded. DNA extracted from blood was subjected to WES to identify variants associated with CKDu. Results: A total of 171 unique variants across 121 genes were identified. Among the most prevalent genes were ATXN3, LFNG, PNLDC1, LINC02456, and HLA-DRB1. In the case–control comparison, only LFNG showed statistically significant enrichment in affected individuals, whereas signals in ATXN3, PNLDC1, and LINC02456 were not statistically significant, but have an association with renal dysfunction, and thus are included as hypothesis-generating variant observations. HLA-DRB1 variants showed trends toward a protective haplotype. LFNG showed the greatest prevalence in affected individuals (71.7%), followed by PNLDC1 (63%), ATXN3 (56%), FIP1L1 (41%), and HLA-DRB1 (32%). Conclusion: Findings suggest genetic variants in combination with environmental factors may contribute to CKDu susceptibility in the Sri Lankan population. We underscore the multi-factorial nature of CKDu and highlight the need for integrative genomic and environmental research to elucidate disease mechanisms and inform targeted prevention strategies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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23 pages, 6220 KB

Open AccessArticle

Genetic Regulation of Monocyte MicroRNAs and Their Implication in Musculoskeletal Diseases: A Cross-Ancestry Expression Quantitative Trait Loci and Imputation Study

by Yong Liu, Kuan-Jui Su, Yun Gong, Bo Tian, Anqi Liu, Zhe Luo, Qing Tian, Chuan Qiu, Hui Shen, Hong-Mei Xiao and Hong-Wen Deng

Int. J. Mol. Sci. 2026, 27(6), 2818; https://doi.org/10.3390/ijms27062818 - 20 Mar 2026

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Abstract

This study investigated the genetic regulation of microRNA (miRNA) expression in monocytes and its potential role in musculoskeletal diseases. We mapped expression quantitative trait loci (eQTLs) for miRNAs using data from 281 Caucasian (CAU) and 170 African American (AA) individuals, constructed ancestry-specific models [...] Read more.

This study investigated the genetic regulation of microRNA (miRNA) expression in monocytes and its potential role in musculoskeletal diseases. We mapped expression quantitative trait loci (eQTLs) for miRNAs using data from 281 Caucasian (CAU) and 170 African American (AA) individuals, constructed ancestry-specific models to impute miRNA expression from genotype data, and applied these models to test associations with osteoporosis and sarcopenia. Analysis identified 468 and 2653 independent eQTLs for 61 miRNAs in CAU and 25 in AA, respectively, the majority of which were ancestry-specific. Association analyses identified 22 and 26 miRNAs associated with osteoporosis and sarcopenia, respectively, in the CAU population; corresponding findings in the African American population were 26 and 14 miRNAs. Analysis of their target genes revealed 1238 and 741 genes that were nominally associated with osteoporosis and sarcopenia in CAU; with 524 genes associated with osteoporosis and 891 associated with sarcopenia in AA. Functional enrichment analysis indicated that the target genes of the identified miRNAs are involved in disease-relevant biological processes—cell migration and motility in osteoporosis, and immune/cytokine responses in sarcopenia. This work provides insights into the genetic architecture of miRNA expression and implicates monocyte miRNAs in musculoskeletal diseases, underscoring the importance of including diverse ancestral backgrounds in genomic studies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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14 pages, 1847 KB

Open AccessArticle

Stability of c-Myc Protein in Early S Phase Is Regulated by the Interaction with PCNA

by Miriana Cardano, Ornella Cazzalini, Giusy Maraventano, Lucia A. Stivala, Laura Zannini and Ennio Prosperi

Int. J. Mol. Sci. 2026, 27(6), 2745; https://doi.org/10.3390/ijms27062745 - 18 Mar 2026

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Abstract

The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization [...] Read more.

The transcription factor c-Myc is known to regulate DNA replication via a non-transcriptional mechanism by interacting with proteins of the pre-replicative complex. In addition, c-Myc localizes to DNA replication foci, similarly to Proliferating Cell Nuclear Antigen (PCNA); however, the significance of this localization remains unclear. Here, we investigated whether c-Myc interacts with PCNA and analyzed the possible function of this association. We found a conserved interaction motif, the PCNA-interacting protein (PIP) box, in the N-terminal region of c-Myc. Confocal microscopy analysis showed co-localization with PCNA in early S-phase, but not in late S-phase cells. Co-immunoprecipitation from cell extracts and pull-down of recombinant proteins indicated a direct physical association between c-Myc and PCNA, which was confirmed in situ by the Proximity Ligation Assay (PLA). Further experiments demonstrated that c-Myc interacts with CUL4A and DDB1, components of the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex, in which PCNA functions as a cofactor. Mutations in the PIP box of c-Myc, as well as depletion of CUL4A by RNA interference, resulted in an increased stability of c-Myc protein. These results suggest that the interaction with PCNA functionally contributes to the regulation of c-Myc stability in early S phase via the CRL4 complex. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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21 pages, 57805 KB

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A Near-Telomere-to-Telomere Genome Assembly of the Spotted Seal (Phoca largha) Reveals Genomic Architecture Underlying Skin and Fur Adaptation

by Min Zhou, Tingting Li, Xiaotong Zhu, Shenghao Liu, Bailin Cong and Linlin Zhao

Int. J. Mol. Sci. 2026, 27(6), 2618; https://doi.org/10.3390/ijms27062618 - 13 Mar 2026

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Abstract

The spotted seal (Phoca largha) is an ice-associated pinniped in the Northwest Pacific and is a subject of conservation concern under increasing environmental and anthropogenic pressures; however, genomic studies have been constrained by the absence of a high-quality reference genome. Here, [...] Read more.

The spotted seal (Phoca largha) is an ice-associated pinniped in the Northwest Pacific and is a subject of conservation concern under increasing environmental and anthropogenic pressures; however, genomic studies have been constrained by the absence of a high-quality reference genome. Here, we present a near-telomere-to-telomere (near-T2T), gap-free genome assembly of P. largha spanning 2.39 Gb and comprising 16 chromosome-length sequences, with a scaffold N50 of 184.39 Mb and high completeness (99.34% complete BUSCOs). Compared with the previous chromosome-level assembly, the new genome improves contiguity and gene-space completeness. Comparative analyses across 20 carnivoran species resolve P. largha as sister to Phoca vitulina with an estimated divergence time of ~2.1 Ma. Branch-site positive-selection analyses and gene-family evolution analyses identify lineage-associated changes, and enrichment results motivate focused investigation of integument-related gene families. Targeted analyses of keratin (KRT) and matrix metalloproteinase (MMP) families reveal contrasting chromosomal organisation and evolutionary dynamics: KRTs form large chromosomal clusters with broadly conserved synteny across Carnivora but lineage-dependent remodelling within clusters, whereas MMPs are dispersed and display largely conserved orthologous correspondence. This high-quality genome provides a high-quality resource for pinniped comparative genomics and for elucidating the genomic architecture of skin and fur adaptation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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14 pages, 1239 KB

Open AccessArticle

Emerging Multi-Source Transmission of SFTS Virus on a Remote Japanese Island: A One-Health Perspective

by Ryosaku Oshiro, Motoki Ihara, Catarina Harumi Oda Ibrahim, Kosuke Matsui, Xayavong Dalouny, Nhung Hong Pham Vu, Tomomi Kurashige, Qiang Xu, Shangfan Hu, Mya Myat Ngwe Tun, Yumika Takaki, Hikaru Ogushi, Daichi Setoguchi, Shinichi Katsuoka, Tatsuki Murakami, Chikara Matsumoto, Mitsuru Hattori, Naoko Hattori, Sho Miyamoto, Yusuke Sakai, Tadaki Suzuki, Hirotomo Yamanashi, Hiroyuki Murota, Takahiro Maeda, Kouichi Morita, Akira Yoshikawa and Yuki Takamatsu Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(4), 1702; https://doi.org/10.3390/ijms27041702 - 10 Feb 2026

Cited by 1 | Viewed by 1072

Abstract

Tick-borne viral infections, including severe fever with thrombocytopenia syndrome virus (SFTSV), are increasingly recognized as a significant threat to global public health owing to their rapid dissemination and high mortality rates. While isolated outbreaks within single species have been documented, reports of multi-host [...] Read more.

Tick-borne viral infections, including severe fever with thrombocytopenia syndrome virus (SFTSV), are increasingly recognized as a significant threat to global public health owing to their rapid dissemination and high mortality rates. While isolated outbreaks within single species have been documented, reports of multi-host cluster cases remain scarce. This study describes a consecutive, cross-species outbreak of severe fever with thrombocytopenia syndrome disease between April and May 2024 on a remote island in Nagasaki Prefecture that involved four cats and four humans. An interdisciplinary investigation integrating molecular phylogenetic analysis of viral genomes—including previously identified Nagasaki strains of SFTSV—and haplotype network analysis provided insights into the infection dynamics. Despite the absence of confirmed direct contact between cats and humans, four animals and one patient succumbed to the infection. Genomic analyses demonstrated high similarity to circulating Nagasaki strains, whereas haplotype analysis indicated multiple viral introduction events and complex transmission pathways, reflecting diverse sources. These findings underscore the critical need for a One Health approach—integrating human, animal, and vector surveillance—to effectively monitor, understand, and control tick-borne viruses globally, in both endemic and emerging regions. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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24 pages, 3439 KB

Open AccessArticle

Mitogenome of Medicago lupulina L. Cultivar-Population VIK32, Line MlS-1: Dynamic Structural Organization and Foreign Sequences

by Maria E. Vladimirova, Marina L. Roumiantseva, Alla S. Saksaganskaia, Alexandra P. Kozlova, Victoria S. Muntyan, Sergey P. Gaponov, Andrey P. Yurkov, Vladimir A. Zhukov and Mikhail P. Grudinin

Int. J. Mol. Sci. 2025, 26(24), 11830; https://doi.org/10.3390/ijms262411830 - 7 Dec 2025

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Abstract

This study presents the complete assembly and analysis of the mitochondrial genome (mitogenome) of Medicago lupulina L. var. vulgaris Koch, cultivar-population VIK32, line MlS-1, which forms an effective symbiosis not only with arbuscular mycorrhiza but also with the root nodule bacteria Sinorhizobium meliloti [...] Read more.

This study presents the complete assembly and analysis of the mitochondrial genome (mitogenome) of Medicago lupulina L. var. vulgaris Koch, cultivar-population VIK32, line MlS-1, which forms an effective symbiosis not only with arbuscular mycorrhiza but also with the root nodule bacteria Sinorhizobium meliloti. The assembly, generated using a hybrid sequencing approach, revealed sequences of putative horizontal origin. These include a highly conserved open reading frame (ORF), orf279, encoding a protein structurally homologous to maturase K, yet bearing remote similarity to bacterial reverse transcriptases and CRISPR-associated proteins. We also identified sequences homologous to mitovirus RNA-dependent RNA polymerases and a fragment of the chloroplast 23S ribosomal RNA (rRNA), suggesting historical gene transfers from viruses and plastids. This work establishes a foundation for investigating the role of mitochondrial genome variation in key plant’s phenotypic traits, such as the enhanced responsiveness to arbuscular mycorrhiza observed in this agronomically valuable line. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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10 pages, 256 KB

Open AccessCommunication

Association of DPP4 Gene Variants with Classic and DPP4 Inhibitor-Associated Bullous Pemphigoid

by Charoula Achilla, Christina Foutsitzidou, Parthena Meltzanidou, Aikaterini Patsatsi, Elizabeth Lazaridou, Glykeria Tzatzagou, Alexandros Lambropoulos and Anthoula Chatzikyriakidou

Int. J. Mol. Sci. 2025, 26(23), 11698; https://doi.org/10.3390/ijms262311698 - 3 Dec 2025

Cited by 1 | Viewed by 882

Abstract

Bullous pemphigoid (BP), the most prevalent autoimmune blistering skin disorder, has been associated with dipeptidyl peptidase-4 inhibitor (DPP4i) treatment in type 2 diabetic patients. This study aimed to investigate the association of DPP4 gene variants, rs3788979 and rs12617656, with classic BP (cBP)- and [...] Read more.

Bullous pemphigoid (BP), the most prevalent autoimmune blistering skin disorder, has been associated with dipeptidyl peptidase-4 inhibitor (DPP4i) treatment in type 2 diabetic patients. This study aimed to investigate the association of DPP4 gene variants, rs3788979 and rs12617656, with classic BP (cBP)- and DPP4i-associated BP predisposition. Fifty-six (56) unrelated patients with cBP, 32 DPP4i-associated BP patients, 60 healthy controls, and 49 diabetic patients receiving DPP4i were included. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Statistical analyses were conducted using SPSS software. For rs3788979, the CT+TT genotypes were significantly associated with increased risk of DPP4i-associated BP compared with cBP [(Odds Ratio (OR) = 2.80, 95% Confidence Interval (CI) = 1.07–7.35; p-value = 0.034] and healthy controls (OR = 0.30, 95% CI = 0.13–0.86; p-value = 0.020). The T allele was also enriched in DPP4i-associated BP (OR = 2.57, 95% CI = 1.09–6.07; p-value = 0.027). Additionally, the TC genotype of rs12617656 (OR = 2.29, 95% CI = 1.04–5.03, p-value = 0.039) showed significant association with cBP susceptibility. These findings highlight DPP4 variants as potential BP risk factors, supporting personalized risk assessment prior to initiating gliptin therapy. Large-scale studies are warranted to validate these associations. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

19 pages, 3843 KB

Open AccessArticle

Mitochondrial Gene Regulation and Pain Susceptibility: A Multi-Omics Causal Inference Study

by Chien-Cheng Liu

Int. J. Mol. Sci. 2025, 26(17), 8690; https://doi.org/10.3390/ijms26178690 - 6 Sep 2025

Cited by 1 | Viewed by 2241

Abstract

The causal contributions of specific mitochondrial genes to common pain phenotypes remain unclear. We employed a multi-omics Mendelian randomization (SMR) approach, integrating QTL data (expression, methylation, protein) for mitochondrial genes with GWAS summary statistics for seven pain phenotypes. We identified 18 candidate genes [...] Read more.

The causal contributions of specific mitochondrial genes to common pain phenotypes remain unclear. We employed a multi-omics Mendelian randomization (SMR) approach, integrating QTL data (expression, methylation, protein) for mitochondrial genes with GWAS summary statistics for seven pain phenotypes. We identified 18 candidate genes with robust SMR associations across omics layers. However, strong colocalization evidence (PP.H4 > 0.7) was largely absent, pointing towards complex genetic architectures. A notable exception was a strong signal for a shared causal variant found at the methylation level for the MCL1 gene in hip pain (PP.H4 = 0.962), nominating it as a high-confidence candidate. Additionally, genetically predicted higher protein levels of Glycine amidinotransferase (GATM) showed consistent protective associations with neck or shoulder, back, and knee pain. This study provides novel evidence for mitochondrial gene regulation in pain, highlighting the GATM pathway as protective and identifying MCL1 methylation as a potential causal mechanism in hip pain. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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23 pages, 4531 KB

Open AccessArticle

Examining the Roles of Genomic Context and Endogenous Regulatory Elements on IS1 Transposition Within the Escherichia coli Genome

by Sofia Smith, Zhongge Zhang, Allyson Ho, Tusha Karnani, Jack Ord and Milton H. Saier, Jr.

Int. J. Mol. Sci. 2025, 26(17), 8375; https://doi.org/10.3390/ijms26178375 - 28 Aug 2025

Cited by 1 | Viewed by 2398

Abstract

Insertion sequence (IS) elements are key drivers of bacterial genome plasticity, yet the overall regulation of their transposition remains poorly understood. This is especially true for the multiple-layer regulation at the donor site, which has been largely overlooked. Using multiple mutation assays, genetic [...] Read more.

Insertion sequence (IS) elements are key drivers of bacterial genome plasticity, yet the overall regulation of their transposition remains poorly understood. This is especially true for the multiple-layer regulation at the donor site, which has been largely overlooked. Using multiple mutation assays, genetic manipulations and reporter genes, this study focuses on characterizing how endogenous DNA sequences, transcriptional and translational factors, and genomic context regulate IS1 transposition from its donor site. Out of six elements within the chromosome of E. coli strain BW25113, IS1A and IS1E (both with the consensus sequence) contribute to over 99.9% of the overall IS1 transposition within the genome while the other four elements without the non-consensus sequence are essentially incapable of transposing. Inducing a ribosomal -1 frameshift at the A₆C motif increases transposition over 1000-fold, but this enhancement is largely reversed by restoring InsA-mediated transcriptional regulation. Strikingly, genomic sequences flanking IS1 elements appreciably modulate transposition by promoting transcription or facilitating formation of transpososomes, a phenomenon that remains under-studied. Finally, IS1 was confirmed to undergo replicative transposition intramolecularly, a mechanism shown here to be independent of transposase levels in the cell. These findings contribute to our understanding of mobile genetic element regulation and potentially offer strategies for mitigating their potentially harmful effects. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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Review

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24 pages, 1538 KB

Open AccessReview

Epigenetic Connections in Malocclusion

by Elzbieta Pawlowska, Maria Mitus-Kenig and Janusz Blasiak

Int. J. Mol. Sci. 2026, 27(14), 6380; https://doi.org/10.3390/ijms27146380 (registering DOI) - 17 Jul 2026

Abstract

Malocclusion arises from complex interactions among genetic, environmental, and developmental factors. While genetic contributions are well established, epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and RNA chemical modifications, have emerged as plausible regulators of craniofacial growth and dentoalveolar remodeling. This structured [...] Read more.

Malocclusion arises from complex interactions among genetic, environmental, and developmental factors. While genetic contributions are well established, epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and RNA chemical modifications, have emerged as plausible regulators of craniofacial growth and dentoalveolar remodeling. This structured narrative review critically evaluates current evidence on the role of epigenetic regulation in the development of malocclusion and in orthodontic tooth movement. Most available data derive from in vitro studies, animal models, and investigations of related craniofacial processes rather than from direct analyses of defined malocclusion phenotypes in humans. Consequently, the evidence base is largely indirect and heterogeneous. To address this limitation, we applied a qualitative appraisal framework that considered study design, methodological rigor, and the directness of the evidence. Experimental findings indicate that epigenetic mechanisms are dynamically regulated by mechanical forces and may influence osteogenesis, chondrogenesis, periodontal remodeling, and individual variability in orthodontic response. However, robust causal studies directly linking specific epigenetic modifications to malocclusion phenotypes remain lacking. Although biological plausibility is strong, a substantial gap persists between mechanistic insights and clinical translation. At present, the clinical utility of epigenetic markers in orthodontic diagnosis, treatment strategy, or prognosis remains limited. Future research should prioritize well-designed longitudinal human studies integrating epigenetic profiling with clearly defined malocclusion phenotypes to establish causal relationships and enable clinically relevant applications. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

20 pages, 11855 KB

Open AccessReview

Converging Signaling Networks Drive Taste Bud Morphogenesis, Turnover, and Regeneration

by In Young Jo, Jin-Woo Kim, Jae Kyeom Kim and Jeong-Oh Shin

Int. J. Mol. Sci. 2026, 27(13), 5644; https://doi.org/10.3390/ijms27135644 - 23 Jun 2026

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Abstract

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a [...] Read more.

Buds are continuously renewed sensory organs in which development, adult maintenance, and repair share overlapping molecular circuitry. During embryogenesis, WNT/β-catenin signaling promotes taste placode formation and placodal Shh expression, while SHH refines papilla spacing and restricts neighboring papilla formation. SOX2 functions as a taste-competence and progenitor maintenance factor. In adults, LGR5/LGR6–RSPO–WNT signaling sustains progenitor activity, and gustatory neurons are an important source of RSPO2; available genetic evidence is consistent with a neuron-derived contribution to the LGR5/LGR6 niche, and AAV-Cre-mediated neuron-specific ablation of Rspo2 in the petrosal ganglion led to near-complete loss of circumvallate taste buds. HH signaling from epithelial and neuronal sources further supports SOX2-dependent progenitor homeostasis. Lineage allocation is governed by transcriptional programs that include POU2F3/SKN-1a for sweet, umami, and bitter type II taste receptor cells, and ASCL1 with posterior-field NKX2-2 for type III presynaptic/sour cells. After denervation or irradiation, regeneration depends primarily on LGR5⁺/KRT14⁺ progenitors and may be supplemented, in specific injury contexts, by plasticity of a subset of K8-lineage taste receptor cells that acquire KRT14/SOX2/PCNA progenitor-like features. Key unresolved questions include the direct chromatin targets of taste lineage regulators (which remain to be defined by ChIP-seq in native taste progenitors), the identity of the type I cell selector, the contribution of dedifferentiation across injury models, and the degree to which mouse-derived networks are conserved in human taste biology. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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36 pages, 3635 KB

Open AccessReview

Integrated Symbiotic Pleiotropy: Long Non-Coding RNAs and Disordered Proteins Interweaving the Functional Layers of the Eukaryotic Cell

by Evelina Daskalova, Joon Seon Lee, Gergana Zahmanova and Ivan Minkov

Int. J. Mol. Sci. 2026, 27(8), 3478; https://doi.org/10.3390/ijms27083478 - 13 Apr 2026

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Abstract

Long non-coding RNAs (lncRNAs) and RNA–protein complexes (RNPs) are increasingly recognized as central to the regulatory complexity of modern eukaryotes. This review proposes that the remarkable diversity of eukaryotic systems arises from the long-term integration of ancient RNA/RNP mechanisms, layered with innovations introduced [...] Read more.

Long non-coding RNAs (lncRNAs) and RNA–protein complexes (RNPs) are increasingly recognized as central to the regulatory complexity of modern eukaryotes. This review proposes that the remarkable diversity of eukaryotic systems arises from the long-term integration of ancient RNA/RNP mechanisms, layered with innovations introduced by successive symbioses. We outline four interconnected levels of symbiosis contributing to this process: (1) molecular symbiosis, involving dynamic assemblies of RNAs, proteins, and membraneless organelles (MLOs); (2) genome symbiosis, driven by the expansion of non-coding and repetitive DNA; (3) intracellular symbiosis, initiated by mitochondria acquisition; and (4) intercellular symbiosis, rooted in the cellular cooperation that enables multicellularity. We highlight lncRNAs and intrinsically disordered proteins (IDPs) as versatile mediators that interweave interactions across scales, predominantly within phase-separated condensates. Building upon these multi-level processes, we propose the framework of integrated symbiotic pleiotropy—a concept where molecular components acquire layered functional roles as a direct consequence of successive symbiotic acquisitions. This paradigm unites information layering, functional moonlighting, molecular tinkering, and exaptation into a coherent trajectory for eukaryotic evolution. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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54 pages, 3951 KB

Open AccessReview

Conserved Pathways, Divergent Outcomes: A Cross-Species Genomic Perspective on the Cancer–Neurodegeneration Paradox

by Bhargavi Rajarathinam, Durga Nandan, Parvathy Venugopal, Amritha M. Nair, Subin John, Bipin G. Nair and Rajaguru Aradhya

Int. J. Mol. Sci. 2026, 27(7), 2989; https://doi.org/10.3390/ijms27072989 - 25 Mar 2026

Cited by 3 | Viewed by 1701

Abstract

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the [...] Read more.

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune–stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons. Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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24 pages, 684 KB

Open AccessReview

Anti-Inflammatory Diets in Metabolic Syndrome and Obesity: Multi-Omics Perspectives on the Interplay Between Gut Microbiota, DNA Methylation, and Adipokine Regulation—A Narrative Review

by Karol Makiel

Int. J. Mol. Sci. 2026, 27(6), 2734; https://doi.org/10.3390/ijms27062734 - 17 Mar 2026

Cited by 1 | Viewed by 2343

Abstract

An anti-inflammatory dietary pattern represents a key component of non-pharmacological management in obesity and metabolic syndrome (MetS), as it targets chronic low-grade inflammation, adipose tissue dysfunction, insulin resistance, and disturbances of the gut–metabolic axis. In the present work, we outline a framework for [...] Read more.

An anti-inflammatory dietary pattern represents a key component of non-pharmacological management in obesity and metabolic syndrome (MetS), as it targets chronic low-grade inflammation, adipose tissue dysfunction, insulin resistance, and disturbances of the gut–metabolic axis. In the present work, we outline a framework for an “omics-based” approach that integrates data on gut microbiota composition and function (metagenomics), adipokine profiles, nutrigenomics, epigenetics, and related transcriptomic and metabolomic layers in order to enable more precise characterization of the metabolic phenotype and to support precision nutrition strategies. The proposed dietary model emphasizes the quality rather than merely the quantity of macronutrients, with particular focus on lipid profile optimization. Specifically, total fat intake is recommended to remain below 30% of total energy through the reduction in saturated fatty acids (SFA), trans fats, and excessive omega-6 fatty acids, alongside increased consumption of omega-3 PUFA (EPA/DHA) and plant-based sources of α-linolenic acid (ALA). Concurrently, greater intake of lean protein sources and low-glycemic-index carbohydrates rich in dietary fibre—particularly fermentable fractions—is recommended. The model also highlights the importance of polyphenols with antioxidant and immunomodulatory properties. To enhance feasibility and long-term adherence, recommendations are structured as flexible food substitutions rather than rigid prescriptions. Further well-designed interventional studies are required to confirm the impact of a multi-omics-based anti-inflammatory diet on both molecular and clinical endpoints. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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15 pages, 1108 KB

Open AccessReview

A Translational Roadmap for Neurological Nonsense Mutation Disorders

by Jiaqing Li, Zhenyun Zhu and Sanqing Xu

Int. J. Mol. Sci. 2026, 27(3), 1418; https://doi.org/10.3390/ijms27031418 - 30 Jan 2026

Cited by 1 | Viewed by 1220

Abstract

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal [...] Read more.

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal muscular atrophy, Rett syndrome, and Duchenne muscular dystrophy. Readthrough therapies—strategies to override PTCs and restore full-length protein expression—have evolved from early aminoglycosides to modern precision tools including suppressor tRNAs, RNA editing, and CRISPR-based platforms. Yet clinical translation remains hampered by inefficient CNS delivery, variable efficacy, and the absence of personalized stratification. In this review, we propose a translational framework—the 4 Ds of Readthrough Therapy—to systematically address these barriers. The framework dissects the pipeline into Detection (precision patient identification and biomarker profiling), Delivery (engineered vectors for CNS targeting), Decoding (context-aware molecular correction), and Durability (long-term safety and efficacy). By integrating advances in machine learning, nanocarriers, base editing, and adaptive trial designs, this roadmap provides a structured strategy to bridge the translational gap. We advocate that a synergistic, modality-tailored approach will transform nonsense suppression from palliative care to durable, precision-based cures for once-untreatable neurological disorders. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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29 pages, 2053 KB

Open AccessReview

Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics

by Eva Bagyinszky and Seong Soo A. An

Int. J. Mol. Sci. 2025, 26(20), 9960; https://doi.org/10.3390/ijms26209960 - 13 Oct 2025

Cited by 1 | Viewed by 3601

Abstract

Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer’s disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN [...] Read more.

Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer’s disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN was a multifunctional protein involved in lysosomal function, neuroinflammation, and neuronal survival. This review discusses the contributions of GRN haploinsufficiency to FTD pathogenesis with an emphasis on genetic mutations, downstream cellular consequences, relevant animal and cellular models, and emerging therapeutic strategies. Loss-of-function mutations in GRN were responsible up to ~50% reduction in PGRN levels, resulting in lysosomal dysfunction, TDP-43 aggregation, impaired microglial homeostasis, and enhanced neuroinflammation. Multiple in vitro and in vivo models recapitulated these pathological features. Novel therapeutic approaches, such as AAV-mediated gene therapy, stop codon readthrough compounds, SORT1 inhibitors, and antisense oligonucleotides, were investigated to restore PGRN levels and to mitigate disease progressions. However, challenges included the oncogenic risks of overexpression and the limited translational success in clinical trials to date. Targeting GRN haploinsufficiency became a promising avenue for FTD therapy. Improved models and refined delivery systems would be essential to develop safe and effective treatments. Future work should also focus on biomarker-guided interventions in presymptomatic mutation carriers. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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12 pages, 7010 KB

Open AccessBrief Report

Identification of Pathogenic Variants in CYP4F22, FLG, ALOX12B, and NIPAL4 in a Case Series of Inherited Ichthyosis

by Malali Abdul Sattar, Amna Aurang Zaib, Huda Abbasi, Mirza Zain Ul Abideen, Saima Riazuddin, Zubair M. Ahmed and Muhammad Naeem

Int. J. Mol. Sci. 2026, 27(10), 4639; https://doi.org/10.3390/ijms27104639 - 21 May 2026

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Abstract

Inherited ichthyoses are clinically and genetically heterogeneous disorders of cornification caused by disruption of epidermal barrier genes involved in keratinization and lipid homeostasis. Pathogenic variants in more than 50 genes have been implicated in nonsyndromic ichthyosis vulgaris (IV) and autosomal recessive congenital ichthyosis [...] Read more.

Inherited ichthyoses are clinically and genetically heterogeneous disorders of cornification caused by disruption of epidermal barrier genes involved in keratinization and lipid homeostasis. Pathogenic variants in more than 50 genes have been implicated in nonsyndromic ichthyosis vulgaris (IV) and autosomal recessive congenital ichthyosis (ARCI). Here, we investigated the genetic basis of ichthyosis in four consanguineous Pakistani families presenting with IV or ARCI phenotypes. Exome sequencing followed by segregation analysis identified pathogenic variants in four established ichthyosis-associated genes: CYP4F22, FLG, ALOX12B, and NIPAL4. Identified variants include one novel nonsense allele of CYP4F22 (c.296G>A; p.Trp99*) and three known variants previously not reported in the Pakistani population. These known variants include a nonsense change in FLG, a frameshift allele of ALOX12B, and a missense variant in NIPAL4. Standardized phenotypic annotation using Human Phenotype Ontology terms revealed overlapping but variable clinical features across families, consistent with known genotype–phenotype heterogeneity in inherited ichthyosis. In silico protein modeling using AlphaFold2 and Ramachandran plot analysis predicted structural perturbations associated with the identified variants, supporting their pathogenic relevance. Publicly available scRNAseq datasets revealed greater heterogeneity of keratinocyte-associated expression patterns of these ichthyosis-associated genes in aging samples. Collectively, our findings expand the allelic and phenotypic spectrum of inherited ichthyosis in the Pakistani population and highlight the utility of comprehensive genetic analysis in consanguineous families for accurate molecular diagnosis, genetic counseling, and disease epidemiology. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Genetics and Genomics)

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