Frontiers in Genetics最新文献

Background: Growing evidence implicates enoyl-CoA hydratase domain-containing protein 2 (ECHDC2) in oncogenesis, yet its role in glioblastoma (GBM) remains undefined. We aimed to clarify the pathological significance and molecular mechanisms of ECHDC2 in GBM.

Methods: Gene-expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed. Kaplan-Meier curves were used to evaluate the prognostic value of ECHDC2. Immune cell infiltration was quantified using CIBERSORT, single-sample gene-set enrichment analysis (ssGSEA), and ESTIMATE algorithms. Spearman's correlation analysis was applied to assess the associations between ECHDC2 expression levels, immune checkpoint molecules, and immune cell subsets. To elucidate the functional relevance of ECHDC2, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene-set enrichment analyses (GSEA) were performed, while protein-protein interaction (PPI) networks were investigated using the STRING database. Subsequently, ECHDC2 was knocked down or overexpressed in GBM cell lines, and its effects on cell proliferation and migration were determined using CCK-8, EdU, wound-healing, and Transwell migration assays.

Results: Upregulated ECHDC2 expression was significantly correlated with unfavorable clinicopathological features and reduced overall survival (OS) in patients with GBM. High ECHDC2 expression was associated with increased infiltration of effector-memory CD8⁺ T cells (TEM) and plasmacytoid dendritic cells (pDCs). Enrichment analyses demonstrated that ECHDC2 is involved in tumor progression, with a particular focus on the PI3K/Akt signaling pathway. In vitro experiments showed that ECHDC2 knockdown suppressed the proliferation and migration of GBM cells. Conversely, ECHDC2 overexpression exerted the opposite effects on GBM cell proliferation and migration.

Conclusion: ECHDC2 overexpression promotes GBM progression and portends poor prognosis. ECHDC2 may serve as both a prognostic biomarker and a therapeutic target in GBM.

Background: Osteogenesis imperfecta (OI) is a hereditary disorder primarily caused by mutations in COL1A1 or COL1A2, leading to bone fragility and deformities. Although numerous pathogenic variants have been identified, novel mutations in specific populations remain underreported, complicating diagnosis and genetic counseling.

Methods: A Chinese family with mild type I OI was recruited. Whole-exome sequencing and Sanger sequencing were used to identify and validate a novel splice-site variant in COL1A1. Functional effects were assessed using two minigene constructs (pcMINI-COL1A1 and pcMINI-N-COL1A1) transfected into HEK293T cells, followed by reverse transcription-polymerase chain reaction (RT-PCR) and sequencing of transcripts.

Results: A novel heterozygous splice-site variant (c.298 + 1G>A) at the donor site of COL1A1 intron 2 was identified and found to co-segregate with the disease. Minigene assays demonstrated that this mutation induces abnormal splicing patterns, including partial and complete skipping of exon 2, resulting in frameshifted transcripts with premature termination codons.

Conclusion: The c.298 + 1G>A variant leads to aberrant splicing and likely haploinsufficiency, consistent with a mild OI phenotype. This study expands the COL1A1 mutation spectrum and supports the use of functional assays for clarifying pathogenicity.

Introduction: Pulmonary arterial hypertension (PAH) secondary to congenital left-to-right shunt heart disease (CL-RSHD) is a life-threatening complication with unclear microbial and metabolic mechanisms. This study investigated gut microbiota and plasma metabolic alterations in CL-RSHD-associated PAH to identify biomarkers and mechanistic pathways.

Methods: This cross-sectional study included 86 participants: healthy controls (HC, n = 13), CL-RSHD (n = 46), and CL-RSHD + PAH (n = 27). Gut microbiota was analyzed using 16S rRNA gene sequencing of the V3-V4 region on 41 fecal samples (HC, n = 9; CL-RSHD, n = 15; and CL-RSHD + PAH, n = 17). Untargeted plasma metabolomics was analyzed on all 86 plasma samples. Microbial diversity, differential taxa (DESeq2), metabolic pathways (OPLS-DA, KEGG), and biomarker potential (ROC curves) were assessed. Dynamic correlations linked microbiota-metabolite interactions.

Results: CL-RSHD + PAH patients showed preserved α/β-diversity but distinct taxonomic shifts: enriched Lachnoclostridium phocaeense (Firmicutes) and reduced SCFA-producing Anaerostipes. Metabolomics revealed dysregulated steroid biosynthesis, cortisol metabolism, and oxidative stress pathways. Key metabolites, including elevated 5-hydroxymethylcytidine (5-hmC) and γ-L-glutamyl-L-cysteine, and reduced histidine intermediate D-E1IG3P, correlated with PAH severity. Strong microbiota-metabolite interactions (e.g., Lactonifactor-D-E1IG3P, r = 0.82, P < 0.01) suggested a disrupted vascular remodeling axis. Metabolites like ADP-glucose (AUC = 0.94) and 3-phenylpropyl glucosinolate (AUC = 0.92) showed high diagnostic accuracy.

Conclusion: CL-RSHD-associated PAH involves gut microbial restructuring and metabolic reprogramming linked to immune-inflammatory activation and oxidative stress. The Firmicutes-histidine metabolism axis emerges as a therapeutic target. Despite limitations, this study provides foundational insights into microbial-metabolic drivers of PAH, highlighting novel biomarkers for early diagnosis and intervention.

[This corrects the article DOI: 10.3389/fgene.2025.1548487.].

Background: Maternal nutrition during gestation plays a critical role in fetal muscle development and long-term metabolic programming; however, its persistent molecular effects on offspring skeletal muscle remain unclear. Therefore, the main objective of this study was to investigate the influence of prenatal nutrition on long-term differential gene expression (DGE), differential mRNA transcript expression (DTE), and differential transcript usage (DTU) in skeletal muscle of beef cattle.

Methods: A total of 126 pregnant Nellore cows were assigned to three dietary treatments: mineral supplementation only (NP), protein-energy supplementation during late gestation (PP), and protein-energy supplementation throughout gestation (FP). At 676 ± 28 days of age, muscle samples were collected from offspring for RNA sequencing. The DGE and DTE analyses were performed using the edgeR package, while DTU was evaluated with the IsoformSwitchAnalyzeR package. Over-representation analysis was conducted using g:Profiler.

Results: A total of 27,412 genes and 111,185 transcripts, including novel loci and isoforms were identified. Gene-level differences were modest (16 genes), whereas transcript-level analyses revealed stronger effects, with a higher number of significant expression and usage changes across conditions. The FP × NP comparison exhibited the greatest impact on gene expression, with 14 DTEs and 87 DTUs, compared with 12 and 30 in PP × NP, and 10 and three in FP × PP, respectively. Isoform switching was observed in key genes including SLC7A8, SLC25A30, SORBS3, and CDH13 genes, influencing coding potential, functional domains, and mRNA stability, with potential consequences for amino acid transport, cytoskeletal organization, and muscle regeneration. Functional enrichment analyses highlighted significant metabolic pathways related to amino acid and biotin metabolism, intracellular trafficking, and immune regulation.

Conclusion: Overall, prenatal nutrition, particularly protein-energy supplementation throughout gestation in comparison to mineral supplementation, modulates offspring muscle mainly through transcript usage and splicing, suggesting long-term adaptive mechanisms beyond gene-level regulation.

Background: POLR3A gene-related syndrome is a complex genetic disorder with diverse clinical manifestations. Understanding its characteristics is crucial for diagnosis and management. Previous studies have reported various aspects of this syndrome, yet a comprehensive analysis of different Variant sites and their associated phenotypes remains necessary.

Case report: This study presents a case of POLR3A-related syndrome in a pediatric patient. Symptom onset occurred after 2 years of age, initially presenting with gait disturbance. As the disease progressed, gait instability worsened progressively and was accompanied by dysarthria, intellectual developmental impairment, and tremor. Subsequent neuroimaging revealed multiple intracerebral infectious lesions with abscess formation. Whole-genome sequencing identified a homozygous c.1771-6C>G variant in the POLR3A gene. This variant has been previously reported as pathogenic at this locus; however, the complication of multiple intracerebral infections and abscess formation represents a previously unreported manifestation. It is noteworthy that the parents of the proband were consanguineous (first-degree relatives).

Conclusion: A review of 60 unrelated probands with POLR3A-related syndrome was conducted based on previously published cases. The analysis revealed no significant sex difference in disease occurrence. The median age of onset was approximately 8 years, with common initial symptoms including gait disturbance and cognitive developmental impairment. Neuroimaging findings indicated cerebral atrophy in 31 cases (66.0%) and white matter hypomyelination in 17 cases (34.7%). Among the reported genetic variants, c.1909 + 22G>A was the most prevalent, identified in 19 families (17.8%), followed by c.1771-6C>G in 9 families (6.4%). Furthermore, patients with different variant sites displayed heterogeneity in initial symptoms, clinical presentations, and imaging characteristics. This comprehensive review enhances the understanding of the phenotypic and genotypic spectrum of POLR3A-related syndrome.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is traditionally recognized as a risk factor for drug- or infection-induced hemolytic anemia. Emerging evidence implicates potential roles of G6PD in neurodevelopment, yet its association with rare neurological disorders remains underexplored in population-based genetic studies, especially within the Chinese population.

Methods: We conducted a retrospective case-control study utilizing whole-exome sequencing (WES) data from a Chinese cohort. Six most prevalent pathogenic G6PD variants in China were screended in children with rare neurological disorders (n = 211) and in controls without neurological involvement (n = 202). Genotype and carrier frequency comparisons were performed. Stratified analyses were performed based on diagnostic certainty and the presence of de novo mutations. Multivariable logistic regression was employed to calculate sex-adjusted odds ratios (ORs) to control for potential sex-related confounding.

Results: After adjusting for sex, the overall carrier rate of pathogenic G6PD variants was significantly higher in patients with neurological disorders than in controls (adjusted OR = 2.44, 95% CI: 1.18-5.06, p = 0.014). Further comparisons across specific groups revealed distinct patterns: affected male patients had a higher carrier rate than their own unaffected fathers (OR = 2.30, 95% CI: 1.08-4.91, p = 0.043), and mothers of case patients showed a higher carrier rate than mothers of controls (OR = 2.03, 95% CI: 1.09-3.78, p = 0.030). The variants NM_001042351.3: c.1376G>T (G6PD Canton) and NM_001042351.3:c.1388G>A (G6PD Kaiping) were the most prevalent across all groups.

Conclusion: This population-based genetic analysis provides preliminary evidence that G6PD deficiency may be a underrecognized genetic risk factor for rare neurological disorders in Chinese children. The findings suggest a potential maternal genetic contribution and indicate that the phenotypic spectrum of G6PD deficiency may extend beyond hematological manifestations to include neurodevelopmental vulnerability. Important limitations include the lack of functional validation and the use of a clinical control group. Further prospective studies incorporating G6PD enzyme activity assessment and functional investigations are warranted to elucidate the underlying mechanisms.

Introduction: Comprehensive care for autistic youth with severe symptoms and language impairment includes genetic testing to find underlying causes. Identifying a genetic diagnosis helps determine prognosis, guide treatment, assess recurrence risk, and connect families with targeted resources and support networks.

Methods: This cross-sectional study analyzed retrospectively data of a cohort of 60 Autism Spectrum Disorder Minimally Verbal (MV) past age 5 children and adolescents who underwent several genetic investigations and were included in an evaluation protocol including cognitive, adaptive, psychiatric, parental stress and autism characteristics' evaluations to identify whether there were any specific clinical or genetic characteristics in the group of minimally verbal autistic individuals.

Results: The percentage of genetic disorders detected in the series is 22.6%. Two groups of MV autistic individuals were defined: those without a known genetic cause (n = 46, neuropsychological data available for 32 individuals) and those with an associated genetic condition (n = 14, neuropsychological data available for 8 individuals). Most participants in both groups scored below 70 on Nonverbal Intelligence Quotient (NVIQ) (77.5% in the first group versus 77.7% in the latter) and adaptive functioning was impaired in both groups, without significant differences. Autism severity, measured by the ADOS-2, was significantly higher in individuals without causative alteration, particularly in Total Comparison Score. However, no differences were found between groups in restricted and repetitive behaviors. CBCL showed high levels of internalizing and externalizing problems in both groups, with no differences. Similarly, parental stress levels were high in both groups.

Discussion: This is the first study analyzing the genotype-phenotype correlation in MV autistic individuals. In this sample, the prevalence of genetic syndromes was found to be twice as high as in the general autistic population (22.6% versus 10%). Regarding the autistic characteristics' severity which appear to be higher in individuals without genetic causative alteration and the absence of significant differences in cognitive, functional and behavioural characteristics, we hypothesised that, in the MV autistic population without genetic causative alteration, there are specific and unknown characteristics of the MV profile which have a greater impact than the individual genetic condition reported.