Search Results (303)

Zinc finger proteins are frequently implicated in a wide range of neurodevelopmental disorders (NDDs). In this study, we report a case of mild intellectual disability (ID), global developmental delay (GDD), and developmental coordination disorder (DCD) in an individual with unaffected parents. Trio-based whole-exome sequencing (WES) identified a de novo variant (c.1530dup, p.Glu511ArgfsTer16) in the ZNF496 gene of the proband. According to ACMG guidelines, this novel variant is classified as pathogenic. It creates a frameshift that introduces a premature stop codon, resulting in a truncated protein of 525 amino acids (compared to the wild-type 587 residues). Notably, NMDEscPredictor analysis predicted that the transcript escapes nonsense-mediated decay (NMD) despite the frameshift. Computational analyses suggest the potential pathogenetic effects of the identified variant. As documented, ZNF496 interacts with JARID2, a gene associated with NDDs, ID and facial dysmorphism (MIM: #620098). In silico analyses suggest that the identified mutation disrupts this interaction by deleting ZNF496’s C2H2 domain, potentially dysregulating JARID2 target genes. To our knowledge, this is the first reported association between ZNF496 and NDDs, and the variant has been submitted to the ClinVar database (SCV006100880). Functional studies are imperative to validate ZNF496’s role in NDDs and confirm the mutation’s impact on ZNF496-JARID2 interactions. Full article

Transcription factors play crucial roles in regulating gene expression, and any dysregulation in their levels could be involved in cancer progression. The role of androgen receptors (AR) and zinc finger (ZNF) proteins in tumors, like prostate cancer (PC), remains poorly understood. Moreover, due to the multifaceted transcriptional behavior of ARs and ZNFs, their biological role in cancer progression may also depend on the interplay with micro-RNAs (miRNAs). Based on The Cancer Genome Atlas (TCGA) database, we analyzed the expression levels of zinc finger transcripts and ARs in PC. Specifically, exploring their involvement in cancer progression and regulation by miRNAs. The analysis relied on several tools to create a multivariate combination of the original biomarkers to improve their diagnostic efficacy. Multidimensional Scaling (MDS) identified two new dimensions that were entered into a regression analysis to determine the best predictors of overall survival (OS) and disease-free interval (DFI). A combination of both dimensions predicted almost 50% (R² = 0.46) of the original variance of OS. Kaplan–Meier survival analysis also confirmed the significance of these two dimensions regarding the clinical output. This study showed preliminary evidence that several transcription factor expression levels belonging to the zinc family and related miRNAs can effectively predict patients’ overall PC survivability. Full article

B-lineage acute lymphoblastic leukemia (B-ALL) is classified into more than 20 molecular subtypes, and next-generation sequencing has facilitated the identification of these with high sensitivity. Bulk RNA-seq analysis of bone marrow was realized to identify molecular subtypes in Mexican pediatric patients with B-ALL. High hyperdiploidy (27.3%) was the most frequent molecular subtype, followed by DUX4 (13.6%), TCF3::PBX1 (9.1%), ETV6::RUNX1 (9.1%), Ph-like (9.1%), ETV6::RUNX1-like (9.1%), PAX5alt (4.5%), Ph (4.5%), KMT2A (4.5%), and ZNF384 (4.5%), with one patient presenting both the PAX5alt and low hypodiploidy subtypes (4.5%). The genes TYK2, SEMA6A, FLT3, NRAS, SETD2, JAK2, NT5C2, RAG1, and SPATS2L harbor deleterious missense variants across different B-ALL molecular subtypes. The Ph-like subtype exhibited mutations in STAT2, ADGRF1, TCF3, BCR, JAK2, and NRAS with overexpression of the CRLF2 gene. The DUX4 subtype showed mutually exclusive missense variants in the PDGRFA gene. Here, we have demonstrated the importance of using RNA-seq to facilitate the differential diagnosis of B-ALL with successful detection of gene fusions and mutations. This will aid both patient risk stratification and precision medicine. Full article

Clear cell renal cell carcinoma (ccRCC), the most common RCC subtype, displays significant intratumoral heterogeneity driven by metabolic reprogramming, which complicates our understanding of disease progression and limits treatment efficacy. This study aimed to construct a comprehensive cellular and transcriptional landscape of ccRCC, with emphasis on gene expression dynamics during malignant progression. An integrated analysis of 90 scRNA-seq samples comprising 534,227 cells revealed a progressive downregulation of sodium ion transport-related genes, particularly CHP1 (calcineurin B homologous protein isoform 1), which is predominantly expressed in epithelial cells. Reduced CHP1 expression was confirmed at both mRNA and protein levels using bulk RNA-seq, CPTAC proteomics, immunohistochemistry, and ccRCC cell lines. Survival analysis showed that high CHP1 expression correlated with improved prognosis. Functional analyses, including pseudotime trajectory, Mfuzz clustering, and cell–cell communication modeling, indicated that CHP1⁺ epithelial cells engage in immune interaction via PPIA–BSG signaling. Transcriptomic profiling and molecular docking suggested that CHP1 modulates amino acid transport through SLC38A1. ZNF460 was identified as a potential transcription factor of CHP1. Virtual screening identified arbutin and imatinib mesylate as candidate CHP1-targeting compounds. These findings establish CHP1 downregulation as a novel molecular feature of ccRCC progression and support its utility as a prognostic biomarker. Full article

GIGYF2 (Grb10-interacting GYF protein 2) functions as a versatile adaptor protein that regulates gene expression at various levels. At the transcriptional level, GIGYF2 facilitates VCP/p97-mediated extraction of ubiquitylated Rpb1 from stalled RNA polymerase II complexes during DNA damage response. In mRNA surveillance, GIGYF2 participates in ribosome collision-induced quality control, nonsense-mediated decay, no-go decay, and non-stop decay pathways. Furthermore, GIGYF2 interacts with key factors including 4EHP, TTP, CCR4-NOT, DDX6, ZNF598, and TNRC6A to mediate translational repression and mRNA degradation. Additionally, dysregulation of GIGYF2 has been implicated in various pathological conditions, including metabolic diseases, vascular aging, viral infections, and neurodegenerative disorders. This review summarizes the structural and functional characteristics of GIGYF2, highlighting its importance in transcriptional regulation, mRNA surveillance, translational inhibition, and mRNA degradation, while also elucidating its potential as a therapeutic target for disease treatment. Full article

Background: Zinc finger proteins (ZNFs), functioning as pervasive transcriptional modulators, serve as pivotal mediators of tumorigenesis and malignant advancement. However, the mechanistic contributions of these epigenetic orchestrators to lung adenocarcinoma pathogenesis remain incompletely characterized. Methods: To elucidate zinc finger proteins’ biological significance in lung adenocarcinoma (LUAD) pathogenesis, we first extracted relevant transcriptional data from TCGA. After preliminary screening with univariate Cox regression, a LASSO algorithm was applied to optimize the risk score model, incorporating key zinc finger protein markers. For independent validation, we accessed GEO dataset GSE68465, applying identical analytical protocols to confirm model generalizability. We performed multivariable Cox regression to identify independent predictors of clinical outcomes after adjusting for confounding variables. Cell-based validation included (1) comparative analysis of zinc finger protein expression across LUAD/normal cell models and (2) technical verification using standardized qRT-PCR protocols. Results: Following rigorous bioinformatics screening comprising differential expression and survival analysis, the final 21-zinc finger protein cohort was selected for risk score algorithm development aimed at clinical outcome prediction. Stratification based on computed risk scores revealed markedly superior survival outcomes in the low-risk cohort compared to high-risk patients. Comparative analysis revealed overall concordance in the transcriptional profiles of eight ZNFs (|coef| > 0.1) across experimental cell systems and TCGA datasets. Conclusions: Collectively, the prognostic framework incorporating zinc finger proteins demonstrates biomarker utility in lung adenocarcinoma survival prediction, while offering novel avenues for molecular target discovery in therapeutic strategies against this malignancy. Full article

Background: Metabolic syndrome and Parkinson’s disease have common pathophysiological denominators. This study aimed to investigate how metabolic syndrome contributes to Parkinson’s disease progression, as well as the genetic traits shared by PD and MetS. Methods: Four hundred and twenty-three newly diagnosed drug-naïve PD patients were analyzed from the Parkinson’s Progression Markers Initiative (PPMI) database. We compared longitudinal changes in the total and subscale scores of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) between PD patients with and without metabolic syndrome over a five-year follow-up. We assessed the frequency of PD-associated genetic variants in both groups. Results: At baseline, Parkinson’s patients with MetS were typically men (p < 0.01) and older (p = 0.04), with a higher Hoehn and Yahr score (p = 0.01) compared with their counterparts without MetS. They showed higher Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total scores at baseline and in follow-up years 2, 3, 4, and 5 (all p-values < 0.05) as analyzed by the Generalized Estimating Equation model. These differences were primarily driven by elevated motor scores (MDS-UPDRS Part III) (p < 0.01). MetS was associated with a higher frequency of the ZNF646.KAT8.BCKDK_rs14235 variant and a lower frequency of the NUCKS1_rs823118 and CTSB_rs1293298 variants. Conclusions: PD patients with MetS had worse motor symptomatology. Both conditions appear to share genetic susceptibility, involving genes related to lipid metabolism (BCKDK), autophagy and inflammation (CTSB), and chromatin regulation (NUCKS1). Full article

Rectal carcinoma (RC) represents approximately 30% of all colorectal carcinomas (CRC) and is considered a distinct clinical entity. Vascular invasion (VI) is recognized as an independent predictor of poor outcomes in RC. In this study, we applied bioinformatics methods to identify gene pathways most likely associated with VI in rectal carcinoma. As ADAMTS8 showed statistically significant negative relations with the VI in RC patients, we further analyzed its top co-dependent genes—DNAL4, EVI2B, PPP1R35, PTGR3, RPL21, SOX4, and ZNF3—for the experimentally proven molecular modulators. We identified a total of 23 compounds from the Comparative Toxicogenomics Database based on previously reported data for all eight target genes. The search was expanded to include additional chemical agents by structure similarity using the PubChem database, which revealed 9661 additional compounds. These were subsequently used for molecular interaction analysis against target proteins co-expressed with, or associated with, ADAMTS8 in RC with VI. Ultimately, we identified four high-affinity compounds—cyanoginosin LR, doxorubicin, benzo[a]pyrene, and dibenzo(a,e)pyrene—that interacted with all target proteins. These compounds show potential for further assessment of their role in modulating processes related to vascular invasion, which is a strong negative predictor of RC outcomes. Full article

Background and Clinical Significance: Brittle cornea syndrome (BCS) is a rare, autosomal recessive connective tissue disorder characterized by extreme corneal thinning, high myopia, and increased risk of spontaneous or trauma-induced ocular rupture. It is primarily caused by mutations in the ZNF469 or PRDM5 genes, which regulate extracellular matrix integrity. Early recognition and diagnosis of BCS are crucial to prevent severe visual impairment. This report presents two genetically confirmed cases of BCS in Albanian siblings, emphasizing the diagnostic value of whole-exome sequencing and individualized surgical management strategies. Case Presentation: Two siblings—a 28-year-old male and a 25-year-old female—presented with progressive visual deterioration and marked corneal thinning (<200 µm). Both had a history of spontaneous ocular rupture following minor trauma in the contralateral eye. Detailed ophthalmologic evaluation revealed keratoglobus, high myopia, and irregular astigmatism. Genetic testing identified the homozygous pathogenic variant c.974delG (p.Cys325LeufsX2) in the PRDM5 gene in both cases. The male underwent penetrating keratoplasty (PKP), achieving a best-corrected visual acuity (BCVA) of 20/30. The female initially underwent deep anterior lamellar keratoplasty (DALK), which was converted to PKP intraoperatively due to central endothelial perforation, resulting in a BCVA of 20/25. Both patients remained complication-free over a 7-year follow-up period. Conclusions: These cases highlight the importance of early genetic diagnosis and a tailored surgical approach in managing BCS. Long-term monitoring and protective strategies are essential to prevent complications. Incorporating genetic testing into clinical practice can enhance diagnostic accuracy and guide personalized treatment plans in patients with hereditary corneal dystrophies. Full article

Background: Low birth weight in newborns is of multifactorial origin (fetal, maternal, placental, and environmental factors), and in one-third of cases, the cause is of unknown origin, with high infant morbidity and mortality. The main treatment for regaining weight and height in children with low birth weight is the application of growth hormones. However, their role as a protective factor to prevent an increase in body composition and the development of metabolic diseases is still poorly understood. Methodology: A case–control study was conducted in a cohort of patients consulted at the CES Pediatric Endocrinology Clinic, Medellín, Colombia, between 2008 and 2018. We evaluated sociodemographic and clinical variables. Additionally, the identification of differential patterns of genomic methylation between cases (treated with growth hormone) and controls (without growth hormone treatment) was performed. The groups were compared using Fisher’s exact test for qualitative variables and Student’s t-test for the difference in means in independent samples. The correlation was evaluated with the Pearson coefficient. Results: Regarding clinical manifestations, body mass index (BMI) was higher in children who did not receive growth hormone treatment, higher doses of growth hormone treatment helped reduce body mass index (R: −0.21, and p = 0.067), and the use of growth hormone was related to a decrease in triglyceride blood concentrations (p = 0.06); these results tended towards significance. Regarding genome-wide methylation patterns, the following genes were found to be hypermethylated: MDGA1, HOXA5, LINC01168, ZFYVE19, ASAH1, MYH15, DNAJC17, PAMR1, MROCKI, CNDP2, CBY2, ZADH2, HOOK2, C9orf129, NXPH2, OSCP1, ZMIZ2, RUNX1, PTPRS, TEX26, EIF2A4K, MYO1F, C2orf69, and ZSCAN1. Meanwhile, the following genes were found hypomethylated: C10orf71-AS1, ZDHHC13, RPL17, EMC4, RPRD2, OBSCN-AS1, ZNF714, MUC4, SUGT1P4, TRIM38, C3, SPON1, NGF-AS1, CCSER2, P2RX2, LOC284379, GGTA1, NLRP5, OR51A4, HLA-H, and TTLL8. Conclusions: Using growth hormone as a treatment in SGA newborns helps regain weight and height. Additionally, it could be a protective factor against the increase in adolescent body composition. Full article

Background: Lymph node (LN) metastasis is one of the most frequent metastatic patterns in patients with gastric cancer (GC); however, few genes predictive of LN status in GC have been identified. Aims: We aimed to identify candidate genes associated with LN metastasis by analyzing the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database and performing immunohistochemical analysis of GC cases at our hospital. Patients and Methods: A total of 2028 GCs from the C-CAT database were enrolled to identify genetic alterations. A total of 360 GC patients who underwent gastrectomy at our hospital were enrolled to examine the clinical significance of CCNE1 expression via an immunohistochemical study. Results: A total of 977 cases out of 2028 GC patients showed LN metastasis. Genetic alterations of ERBB2, CCNE1, MYC, ZNF217, and GNAS were frequent in the LN metastasis group. CCNE1-positive expression was found in 108 (30.0%) of the 360 GC samples. LN metastasis was significantly (p = 0.01) more frequent in CCNE1-positive patients. In addition, the CCNE1-positive group had a significantly (p < 0.001) poorer prognosis than the CCNE1-negative group, which was especially evident for GC patients at stage I. CCNE1 positivity was significantly (p < 0.001) correlated with postoperative recurrence. Conclusions: CCNE1 gene amplification is associated with LN metastasis of GC. Full article

Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq on ferroptosis-related genes in distinctive MS phenotypes, we selected putative regulatory variants in the top three DEGs (CDKN1A, MAP1B and EGLN2) and investigated their association with gene expression, plasma/serum parameters and disease severity (EDSS, MSSS, gARMSS). The study included 604 patients with relapsing–remitting (RR) and 241 with progressive (P) MS. The variants CDKN1A rs3176326 and rs3176336, EGLN2 rs111833532, MAP1B rs62363242 and rs1217817 with the previously reported DYSF-ZNF638 locus rs10191329, and MTSS1 rs9643199 were genotyped using TaqMan^®, and the HLA-DRB1*15:01 status was also determined. Significant association of the rare MAP1B rs62363242 allele with PMS in females, independent of HLA-DRB1*1501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. CDKN1A haplotypes were significantly associated with CDKN1A mRNA levels in RRMS and SPMS patients. RAB4B-EGLN2 locus rs111833532 and DYSF-ZNF638 locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of CDKN1A, a part of the p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor and critical regulator of the response to hypoxia, variant rs111833532, along with DYSF-ZNF638 locus rs10191329, was associated with clinical severity. The indicated, novel, sex-specific association of MAP1B rs62363242 with the course of MS remains to be validated in larger studies. Full article

The human genome is widely transcribed, with part of these transcribed regions producing stably expressed protein-coding or non-coding RNAs. Long intergenic non-coding RNAs (lincRNAs) are significantly differentially expressed in various cell lines and tissues. However, the influence of their transcription events remains unclear. In this study, we constructed a human genomic interaction network and found frequent interactions between lincRNA genes and protein-coding genes that are highly related to the occupancy of RNA polymerase II on the lincRNA gene. Interestingly, in the human genome interaction networks, the degree of lincRNA genes was significantly higher than that of protein-coding genes. The promoter regions of the protein-coding genes interacting with the lincRNA genes are enriched with R-loop structures, indicating that lincRNA may influence the target genes through R-loop structures. These promoters were enriched in more transcription factor binding sites. Furthermore, the whole network and sub-network could be utilized to explore potential biomarkers of leukemia. We found that zinc finger protein 668 (ZNF668), eosinophil granule ontogeny transcript (EGOT), and glutamate metabotropic receptor 7 (GRM7) could serve as novel biomarkers for acute myeloid leukemia (LMAL). Pasireotide acetate (CAS No. 396091-76-2) represents a potential drug for LMAL patients. These results suggested that potential biomarkers and corresponding drugs for cancer could be identified based on lincRNA–promoter network/sub-network topological parameters. Full article

This study investigates the enhancement of corrosion resistance in magnesium-lithium alloys through plasma electrolytic oxidation (PEO) coatings incorporating ZnF₂ via in situ synthesis. By adjusting Zn²⁺ concentrations (4–16 g/L) in a zirconium salt-based electrolyte, ceramic coatings with tailored ZnF₂ content, thickness, and porosity were fabricated. The optimal Zn²⁺ concentration of 12 g/L yielded a ZnF₂-rich coating with isolated pores and enhanced densification (inner layer resistance R_i = 3.01 × 10⁴ Ω⋅cm²), achieving a corrosion current density (i_corr) of 4.42 × 10⁻⁸ A/cm² and polarization resistance (Rp) of 8.5 × 10⁵ Ω⋅cm², representing a 354-fold improvement over untreated LA103Z. Higher Zn²⁺ concentrations (16 g/L) induced interconnected pores and ZnO formation, degrading corrosion resistance. Long-term immersion (168 h in 3.5 wt% NaCl) confirmed the durability of Zn₁₂ coatings (mass loss: 0.6 mg), while Zn₄ and Zn₁₆ coatings exhibited severe localized corrosion. The study demonstrates that balancing Zn²⁺ concentration optimizes ZnF₂ passivation and pore isolation, offering a scalable strategy for Mg-Li alloy protection in corrosive environments. Full article

Micronutrient malnutrition, often caused by the low bioavailability of zinc (Zn) and selenium (Se) in soil, poses serious health risks worldwide. To address these deficiencies, this study evaluated the efficacy of combined Se and Zn fertilization in durum wheat (Triticum durum) through a two-year field experiment conducted under semi-arid Mediterranean conditions. The experimental design was a split-split-plot, considering the growing season (2017/18 and 2018/19) as the main plot, an initial soil application of Zn (50 kg ZnSO₄-7H₂O ha⁻¹ vs. no Zn) as the subplot, and different foliar treatments as the sub-subplot factor: no application (0F), 10 g Se ha⁻¹ (SeF), 8 kg ZnSO₄-7H₂O ha⁻¹ (ZnF), and a combination of ZnF + SeF. While Zn soil application resulted in a 16% increase in both grain and straw yields, the combined Zn and Se foliar application resulted in a significant 15% increase in grain yield, as well as for the highest concentrations of Zn (by 1.44- and 7.38-fold in grain and straw, respectively) and Se (by 3.41- and 4.41-fold in grain and straw, respectively). These results indicate that durum wheat is a promising crop for biofortification initiatives that could contribute to reducing Zn and Se deficiencies in human diets and livestock feed in the Mediterranean region. Full article