Frontiers in Genetics最新文献

Background: Vanishing white matter disease (VWMD; OMIM 603896), also known as childhood ataxia with central nervous system hypomyelination (CACH), is a rare autosomal recessive leukodystrophy caused by pathogenic variants in the EIF2B gene family (EIF2B1-EIF2B5). Clinical manifestations are highly heterogeneous, with onset ranging from fetal life to adulthood; adult-onset cases remain relatively rare and often present with atypical symptoms. Brain magnetic resonance imaging (MRI) and genetic testing are pivotal for diagnosis.

Case presentation: We report a 32-year-old Chinese female with adult-onset VWMD characterized by intermittent headaches, progressive cognitive decline, menstrual irregularities, and hearing loss. Cranial MRI with diffusion-weighted imaging (DWI) revealed symmetrical periventricular and centrum semiovale white matter abnormalities. Whole-exome sequencing (WES) identified a homozygous missense variant in the EIF2B5 gene, formatted per Human Genome Variation Society (HGVS) guidelines as NM_001414.4:c.185A>T (p.Asp62Val). This variant was previously documented exclusively in a pediatric patient, representing the first report in an adult.

Conclusion: Our case expands the phenotypic and age-related spectrum of EIF2B5-associated VWMD, highlighting that the c.185A>T variant is capable of manifesting in adulthood with non-classical features (e.g., headache as the initial symptom). Prior studies have confirmed that this variant impairs EIF2B complex function, which reinforces its pathogenic role in disrupting the integrated stress response (ISR) and maintaining white matter homeostasis. A literature review of 99 genetically confirmed adult-onset VWMD cases further underscores genotype-phenotype correlations: EIF2B5 is the most frequently mutated subunit in adult patients, with cerebellar ataxia, cognitive decline, and psychiatric symptoms as the predominant initial manifestations. Female patients often present with premature ovarian failure, a key diagnostic hallmark. Early genetic testing is crucial for definitive diagnosis, prenatal counseling, and symptomatic management. Notably, this study has limitations, including the lack of investigation into gene-gene interactions-factors that may modulate disease severity and phenotypic variability-and the unavailability of parental genetic data to fully validate zygosity.

Introduction: Ulcerative colitis (UC) is a lifelong, chronic inflammatory disorder, characterized by recurrent and diffuse inflammation of the rectal and colonic mucosa. Increasing evidence suggests that impaired mitophagy contributes to immune dysregulation and epithelial injury in UC. However, the mitophagy-related molecular landscape and its therapeutic potential remain largely unexplored.

Methods: Mitophagy-related genes (MRGs) were intersected with differentially expressed genes to identify UC-associated MRGs. Functional enrichment, immune infiltration, and consensus clustering analyses were performed to characterize molecular subtypes. Three machine learning methods were employed to identify diagnostic models. Candidate therapeutic agents were identified by the CMap database.

Results: A total of 35 UC-associated MRGs were identified, enriched in cell activation, fatty acid metabolism, and the PPAR signaling pathway, revealing strong immunometabolic coupling in UC. Consensus clustering stratified UC patients into two subtypes: a metabolism-dominant subtype (C1) and an inflammation-activated subtype (C2). Three hub genes-CD55, CPT1A, and SLC16A1-were screened and validated as robust diagnostic markers. Drug prediction and molecular docking revealed strong binding between galunisertib and CD55, which was further validated by molecular dynamics simulations. In vitro, galunisertib significantly suppressed inflammatory cytokine release in LPS-induced UC cell models.

Discussion: This study delineated the mitophagy-related molecular signatures of UC and identified CD55, CPT1A, and SLC16A1 as key biomarkers linking mitochondrial dysfunction, metabolic reprogramming, and immune activation. Furthermore, galunisertib was proposed as a potential therapeutic agent, providing a theoretical basis for UC therapy.

[This corrects the article DOI: 10.3389/fgene.2024.1455502.].

Dietary restriction (DR), defined as reduced caloric intake or selective limitation of specific nutrients without malnutrition, is one of the most robust interventions known to extend lifespan and healthspan across species. Studies from yeast to mammals demonstrate that DR elicits conserved genetic, transcriptional, and epigenetic programs that promote cellular maintenance and stress resistance. At the molecular level, DR engages evolutionarily conserved nutrient-sensing pathways, including insulin/IGF-1 signaling (IIS), the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and NAD⁺-dependent sirtuins, which converge on key transcription factors (TFs) and transcriptional coactivators (TCs) to coordinate metabolic and longevity-associated gene expression. Downstream, these pathways enhance autophagy and proteostasis, remodel mitochondrial function and redox balance, reshape immune and inflammatory networks, and induce epigenetic and transcriptional reprogramming. Recent work further highlights amino acid-specific sensing mechanisms, endocrine mediators such as fibroblast growth factor 21 (FGF21), the gut microbiome, circadian regulators, and nuclear pore-associated transcriptional plasticity as integral components of DR responses. Importantly, the physiological outcomes of DR are context dependent and influenced by genetic background, sex, age at intervention, and the type and duration of restriction. In this review, we summarize current knowledge on the genetic and molecular architecture underlying DR-induced longevity and health benefits across species, discuss implications for aging-related diseases, and outline future directions toward precision nutrition and safe translational strategies.

Objectives: Hyperuricemia and gout are common public health problems, stemming from both genetic and lifestyle factors. Evidence from multi-ethnic regions in Yunnan Province remains limited. This preliminary study examined hyperuricemia and gout prevalence, related biomarkers, lifestyle patterns, and SLC2A9/SLC22A12 genetics variations among 88 participants from the Miao community in Yunnan Province China.

Methods: A cross-sectional survey and biochemical study were conducted. Demographic and lifestyle data were collected, and blood samples were analyzed for serum biochemical indicators. Eight SNPs in SLC2A9 and SLC22A12 were genotyped. Logistic regression models were applied to allele and genotype data.

Results: Demographic and clinical analyses for Miao villagers (n = 88) suggested that the morbidities of hyperuricemia and gout were more frequent in male and showed significant association with alcohol consumption, smoking, and elevated BMI. While dietary patterns showed no significant differences. Compared with non-hyperuricemia/non-gout individuals (n = 56), the hyperuricemia/gout group (n = 57) showed 56% higher uric acid (553.13 vs. 354.73 μmol/L), 37% elevated creatinine (84.66 vs. 61.80 μmol/L), and higher triglycerides (3.35 vs. 1.80 mmol/L), along with hematological abnormalities, e.g., elevated hemoglobin (162.77 vs. 147.50 g/L) and lower platelets counts (161.09 vs. 194.14 × 10⁹/L). Preliminary genetic analyses indicated a possible association between SLC2A9_rs10939650 and hyperuricemia/gout risk, whereas variant SLC22A12 polymorphisms showed no association. After Bonferroni correction, no SNPs remained statistically significant.

Conclusion: This preliminary study suggested that the relatively higher burden of hyperuricemia and gout in the Miao population may be influenced by ethnicity, sex, lifestyle factors, metabolic alteration, and potential genetic components. Given the small sample size, the genetic findings should be interpreted cautiously and validated in larger studies for that disease (hyperuricemia and gout) and for similar ethnic community.

Background: This study aimed to identify novel mutations associated with the progression of gastric cancer by establishing patient-derived xenograft (PDX) models and performing comprehensive genomic characterization of these PDX models and their corresponding primary tumors.

Methods: Fresh gastric cancer tissue samples were collected from 20 patients who underwent surgical resection at Shanxi Cancer Hospital and were subsequently implanted into NOD-SCID mice to establish PDX models. Histopathological features were evaluated using hematoxylin and eosin (H&E) staining. Whole-exome sequencing (WES) was performed on both primary tumors and their corresponding F1-PDX and F3-PDX tumors, focusing on mutations within 559 cancer-related genes. Predictive tools, including SIFT, Polyphen2_HVAR, Polyphen2_HDIV, and Mutation Taster, were utilized to identify potentially deleterious mutations, while I-Mutant and MUpro were employed to assess protein stability.

Results: Nine gastric cancer PDX models were successfully established, with seven models propagated to the third generation (F3-PDX), achieving an initial engraftment success rate of 45%. The latency of tumor establishment significantly decreased with each successive generation. The histological characteristics of the primary tumors were well preserved in the PDX models. WES of the three selected models revealed key mutated genes in primary tumors (F0), including IRS2, BLM, PDE4DIP, NUMA1, MYH9, TP53, PIK3CD, ERCC5, and ASXL1. A total of 28 somatic mutations were conserved across all three generations (F0, F1-PDX, and F3-PDX) in these models, representing a conservation rate of 43.75% (28/64). Among these conserved mutations, 10 were identified as potentially deleterious by multiple bioinformatics algorithms. Mutations in PTPRK (p.L988S), PIK3CB (p.F934L), LRP1B (p.A1912T), and IGF2R (p.G2052R) were predicted to significantly decrease protein stability.

Conclusion: This study demonstrated that PDX models effectively preserve the biological and genetic characteristics of primary gastric tumors, underscoring their utility in studying tumor heterogeneity. The integrated analysis of longitudinal WES data from primary tumors and matched PDXs enabled the identification of a core set of conserved, potentially deleterious mutations. The four prioritized mutations (PTPRK, PIK3CB, LRP1B, and IGF2R) provide new insights into the genetic landscape of gastric cancer and represent promising candidates for the development of targeted therapeutic strategies.

Introduction: The APOBEC3 family of cytidine deaminases induces somatic mutations that are highly prevalent in cancers, but the functional consequences remain largely unknown.

Methods: To determine these consequences, we exposed MCF7 tumorigenic breast epithelial cells to APOBEC3A, APOBEC3B or APOBEC3H Haplotype I.

Results: Comparative analysis between cells pre and post -APOBEC3 exposure revealed fewer deamination-dependent γH2AX foci post-APOBEC3 exposure, despite maintaining APOBEC3 protein expression. In a mouse xenograft model, high expressing, but not low expressing APOBEC3A-exposed cells caused increased tumor progression. In contrast, high expressing, but not low expressing APOBEC3B-exposed cells decreased tumor size. APOBEC3H Haplotype I-exposed cells stochastically increased tumor progression independent of expression levels. Consistent with tumor data, RNA-seq showed upregulation of tumor enhancing pathways only in cells that enhanced tumor progression.

Discussion: The results indicate that in a breast cancer xenograft model, APOBEC3A and APOBEC3H Haplotype I are more likely to contribute to enhanced tumor progression than APOBEC3B.

The Tylorrhynchus heterochaetus, a polychaete benthic invertebrate belonging to the Nereididae family, has emerged as a promising aquaculture species. It is highly regarded for its nutritional profile, with protein accounting for up to 60% of its dry weight, as well as its balanced amino acid composition. This has earned it the nickname "aquatic cordyceps". However, wild populations of this species have declined significantly due to environmental shifts and human activities, with local extinctions reported in certain regions. A critical barrier to advancing its population genetics and conservation biology has been the absence of a chromosomal-level reference genome for T. heterochaetus. To address this gap, we present the first chromosome-level genome assembly of T. heterochaetus, generated using PacBio HiFi sequencing data and Hi-C technology. The final assembly spans 782.25 Mb with a scaffold N50 of 75.39 Mb, successfully anchored to 11 pseudo-chromosomes. Repetitive sequences account for 428.09 Mb (54.73%) of the genome, and 20,145 protein-coding genes were annotated. This study provides foundational insights into the genetics, genomics, and evolutionary history of T. heterochaetus, laying a critical groundwork for future research and enabling the development of targeted genetic conservation strategies.

Background: Parkinson's disease (PD) is influenced by various factors, with lysosome function playing a critical role. However, the specific involvement of lysosome-related genes (LRGs) in PD remains unclear.

Objective: This study aims to identify biomarkers specific to PD that exhibit robust disease prediction capabilities.

Methods: Datasets for patients with PD, LRGs, and inflammation-related genes (IRGs) were retrieved from online databases. miRNAs and mRNAs within key modules were selected through Weighted Gene Co-expression Network Analysis (WGCNA), revealing strong associations with PD. A miRNA-mRNA network was constructed based on highly correlated PD-related LRGs (PD-LRGs) and miRNAs within these modules. Candidate genes were identified by intersecting target genes, differentially expressed genes (DEGs), PD-LRGs, and module-associated mRNAs. Machine learning and expression validation were employed to confirm these biomarkers. A nomogram was established, and its diagnostic performance was evaluated using a confusion matrix. Drug predictions were conducted based on these biomarkers. Spearman's correlation analyses were performed to assess the relationship between IRGs, freezing of gait (FOG)-related genes, and biomarkers. Molecular regulatory networks were constructed using datasets and online resources. Finally, clinical samples were collected for quantitative PCR (qPCR) validation of biomarker expression.

Results: Key modules related to PD were identified, comprising 190 miRNAs and 7,633 mRNAs. A miRNA-mRNA network was constructed based on 55 PD-LRGs and 181 miRNAs, resulting in the identification of 26 candidate genes strongly linked to lysosomal function. FGD4 and MAN2B1 were selected as biomarkers, and a gene expression-based risk prediction table was created. These biomarkers were significantly correlated with IRGs and several FOG-related genes. Gene localization analysis revealed that FGD4 and LRRK2, both critical to the FOG pathway, are located on chromosome 12. Drug prediction revealed that Tetrachlorodibenzodioxin and bisphenol A target both FGD4 and MAN2B1. qPCR analysis confirmed that FGD4 and MAN2B1 expression levels were significantly higher in patients with PD compared to healthy controls (p < 0.05).

Conclusion: FGD4 and MAN2B1 act as lysosomal biomarkers associated with PD and exhibit strong correlations with genes involved in PD-related freezing of gait. This study offers novel insights into PD diagnosis.