Frontiers in Genetics最新文献

We report a pediatric case of cholestatic liver disease associated with two novel compound heterozygous variants in the USP53 gene: a truncating c.1219A>T (p.Lys407*) variant inherited from the father and a maternally inherited gross deletion involving exons 13-19. Despite the disruptive nature of these variants, the patient presented with a benign recurrent intrahepatic cholestasis (BRIC) characterized by episodic pruritus, jaundice and elevated bile acids with preserved liver function between episodes. Liver histology revealed fibrosis with a cholestatic component, consistent with mild progressive familial intrahepatic cholestasis (PFIC) features. Molecular diagnosis was confirmed by whole-exome sequencing (WES), chromosomal microarray, and Sanger sequencing. A systematic review of 39 published cases was conducted, revealing that USP53-related disease exhibits broad clinical variability, ranging from BRIC to PFIC7. Our findings expand the spectrum of USP53 variants, underscore the relevance of large deletions and emphasize the inclusion of USP53 in genetic panels for idiopathic low-gamma-glutamyl transferase (GGT) cholestasis.

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in eukaryotic messenger RNA (mRNA). Pigs are valuable not only as a source of meat protein but also as ideal animal models for studying human diseases. To date, m6A has not been systematically mapped in a body-wide survey of porcine tissues. In this study, we used direct RNA sequencing data of 39 sow samples (from 23 tissues) and 7 fetal samples (from 7 tissues) to identify m6A modifications and alternative splicing (AS) events. In total, we identified 60,823 transcripts, including 27,823 novel isoforms. The mean poly(A) tail length varied markedly among tissues, ranging from 48 to 101 nt. A total of 343,951 m6A sites were identified, with sow and fetal samples averaging 80,336 and 92,476 sites, respectively. The number of m6A sites varied across different samples, ranging from 27,830 to 118,042. The brain samples displayed the most pronounced region-specific m6A pattern; different anatomical locations within the same tissue exhibited high m6A heterogeneity. Overall, m6A methylation levels were positively correlated with transcript expression levels; integrative analyses further supported an association between m6A modification and AS. Our findings provide novel insights that enhance our understanding of the regulatory complexity of the transcriptome and epitranscriptome in pigs.

Introduction: Rubinstein-Taybi syndrome type 2 (RSTS2; OMIM #613684) is a rare autosomal dominant disorder caused by loss-of-function variants in the EP300 gene (OMIM #602700), characterized by intellectual disability, distinctive craniofacial features, and skeletal anomalies.

Methods: Whole-exome sequencing (WES) was performed on five pediatric patients presenting with neurodevelopmental delay. Candidate variants were filtered using the TGex platform and validated by Sanger sequencing for familial segregation analysis. The functional impact of variants was assessed using diverse bioinformatic tools, and pathogenicity classifications were assigned according to ACMG/AMP guidelines.

Results: Five novel EP300 variants were identified in this study: c.4774A>G (p.Lys1592Glu), c.4452 + 5G>C, c.3764A>G (p.His1255Arg), c.3591-2A>G, and c.6439C>T (p.Gln2147*). These alterations impair gene function through mechanisms including amino acid substitution, disruption of mRNA splicing, or premature protein truncation. All variants were classified as pathogenic or likely pathogenic per ACMG/AMP criteria. Literature analysis reveals that the predominant clinical manifestations in the Chinese patients encompassed neurodevelopmental impairment, accompanied by motor delay, growth retardation, and microcephaly. Strikingly, archetypal craniofacial dysmorphisms, such as arched eyebrows, long eyelashes, downslanting palpebral fissures, beaked nose, as well as significant skeletal abnormalities were absent, suggesting EP300 variants may present with a broader and more variable phenotypic spectrum than previously recognized.

Conclusion: This study reports five novel pathogenic EP300 variants, expanding the variant repertoire of RSTS2 and providing an important basis for clinical diagnosis and genetic counseling.

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, frequently caused by heterozygous loss-of-function variants in transcription factor (TF) genes. Why are MODY variants in TF genes dominantly inherited? Here I present a systems biology-based explanation. The fact that MODY-associated TFs are master regulators of pancreatic β cell fate suggests that pathogenic variants cause defects in cell fate determination. From a systems biology perspective, cell fate defects are based on disrupted bistability, a crucial feature of dynamical systems to make binary choices. Bistability requires both positive feedback and ultrasensitivity, the latter often in the form of cooperativity. MODY-associated TFs exhibit both features, which not only allows for bistability, but also makes these TFs extremely dosage sensitive, which explains why heterozygous loss of function is sufficient to cause a disease phenotype. A review of the literature strongly supports this hypothesis. Moreover, the hypothesis also helps to explain why incomplete penetrance is such a pervasive feature of MODY-associated variants in TF genes.

Background: Isocitrate dehydrogenase wild-type (IDH wild-type) gliomas represents the most aggressive subtype of diffuse gliomas, characterized by therapeutic resistance and dismal prognosis. Despite advances in molecular classification, reliable prognostic biomarkers for these tumors remain limited, particularly for recurrent disease. This study aims to identify gene expression signatures associated with survival outcomes in recurrent IDH wild-type gliomas, with the goal of improving patient stratification and potential therapeutic targeting.

Methods: We analyzed gene expression data from 180 recurrent IDH wild-type glioma samples from the Glioma Longitudinal AnalySiS (GLASS) Consortium. Using multiple computational approaches including a novel network-based method (netSurvival) and various survival analysis techniques, we identified genes associated with patient survival outcomes.

Results: Our comprehensive analysis identify several gene expression markers that are associated with survival outcomes in recurrent IDH wild-type gliomas. Pathway enrichment analysis identified three significant pathways: FGFR3 signaling, nanoparticle-mediated receptor signaling, and MYCN transcriptional activation, highlighting receptor tyrosine kinase signaling and transcriptional dysregulation as key mechanisms. The AFT log normal model revealed that FN1, HIF3A, and EIF4B are associated with poorer survival (hazard ratios of 1.40, 1.49, and 1.54, respectively; p < 0.05), while PTK2, CCND2, RAD51L3-RFFL, and MAX demonstrated protective effects (hazard ratios of 0.76, 0.78, 0.79, and 0.79, respectively; p < 0.05). Five genes (KIF5C, LINC00632, B4GALNT3, HIF3A, and RAD51L3-RFFL) show significant differential expression between primary and recurrent tumors, with four having established functional roles in glioma pathobiology.

Conclusion: This study identifies a panel of gene expression markers with significant prognostic value in recurrent IDH wild-type gliomas. The differential impacts of these genes on survival outcomes provide insights into the biological heterogeneity underlying clinical behavior in these aggressive tumors. Particularly significant are the biomarkers associated with both survival outcomes and recurrence patterns, which may represent key drivers of disease progression. These findings represent an important step toward improved prognostic stratification and therapeutic targeting in IDH wild-type gliomas, addressing a critical unmet need in neuro-oncology.

Background and purpose: We aimed to explore the mechanisms and pathways of exercise-based interventions in the treatment of polycystic ovarian syndrome (PCOS).

Methods: In this literature review, studies related to exercise therapy for PCOS that were published in the past 20 years were searched, potentially effective active ingredients were screened, and gene prediction of active ingredients and diseases was conducted using the compound and GeneCards databases, respectively, to identify potential targets of exercised-related bioactive molecules in PCOS. Finally, hub genes and signaling pathways were predicted using bioinformatic methods.

Results: The review identified eight potential effective components were screened out, including irisin, 5α-reductase, kisspeptin, cocaine-and amphetamine-regulated transcript, nerve growth factor, nerve peptide Y, insulin-like growth factor-1, and interleukin-6. A total of 192 target genes for exercise-related components and PCOS were identified, including the hub genes TNF, IL6, IL1B, JUN, CCND1, and PSMA7.

Conclusion: The hub genes identified in this review indicate that exercise therapy in PCOS may affect the protease system, renin-angiotensin system, inflammatory signal transduction, neuroactive ligand-receptor interaction, and other pathways through the G protein-coupled receptor signaling pathway, neuropeptide signaling pathway, endocrine process, and other biological processes and regulate apoptosis, cell cycle, and intercellular communication.

Objective: This study investigates the intergenerational transmission of benign mosaic supernumerary marker chromosomes or structural variant chromosomes (SMCs/SVs) and explores the developmental mechanisms that maintain non-pathogenic mosaic levels across generations. While chromosomal mosaicism is widely recognized in reproductive genetics, most previous work has focused on pathogenic outcomes. Here, we highlight an underexplored phenomenon of non-pathogenic SMCs/SVs mosaicism and propose a developmental selection model that may explain its stable inheritance.

Methods: We describe a rare father-offspring pair carrying a mosaic SV at chromosome 11p11, both phenotypically normal. Karyotyping and SNP-array analyses were performed on parental blood, amniotic fluid, and cord blood. A systematic literature review identified 35 additional families with benign parent-child SMCs/SVs mosaicism. To probe potential regulatory mechanisms, four complementary computational approaches including agent-based simulation, logistic regression, Bayesian inference, and Markov chain modeling were applied to evaluate the developmental selection dynamics.

Results: The father exhibited a 57% SV mosaic ratio, while the offspring showed comparable or slightly reduced ratios (38%-45%). Literature analysis revealed consistent patterns of equal or lower mosaicism in offspring across diverse SMCs types, suggesting that transmission occurs within a constrained, non-pathogenic range. Computational modeling demonstrated that even mild negative selection during blastocyst development could reproduce these retention trends, supporting a developmental selection mechanism that limits SMCs/SVs-positive cells to a harmless threshold.

Conclusion: These findings provide convergent clinical and computational evidence that early human embryos may employ a self-correction mechanism to regulate benign SMCs/SVs mosaicism. We propose a developmental "Shepherd Mechanism," whereby mosaic cells are selectively eliminated until a safe equilibrium is reached, ensuring viable yet non-pathogenic inheritance. This work introduces a conceptual framework for understanding naturally tolerated chromosomal variation and offers theoretical guidance for prenatal genetic counseling and embryo selection strategies in assisted reproduction.

Introduction: Bladder cancer (BLCA) is a common malignant tumor of the urinary system. The development and progression of BLCA are controlled by multiple regulatory molecules, which have not been widely investigated.

Methods: In this study, we explored the functions and downstream targets of serine hydroxy methyltransferase 2 (SHMT2) by silencing its expression using small interference RNA (siSHMT2) in HT-1376 cells. Whole transcriptome and metabolism profiles were deeply analyzed to identify the molecular targets of SHMT2.

Results: We found that siSHMT2 significantly reduced the proliferation rate and altered the cell cycle stages of HT-1376 cells. Moreover, siSHMT2 can modulate the expression of hundreds of genes (DEGs), including 126 upregulated and 106 downregulated DEGs. We then found that the most significant DEGs were tightly associated with progression of cancers, including PTMA, HNRNPR, RAPH1, TRAF3IP1, CNBP, and PRR15. At the same time, the alternative splicing profile was also regulated by siSHMT2, including the skipped exon as the dominant AS types. Then we confirmed the changed expression levels of PTMA, HNRNPR, RAPH1, and CNBP, and AS level of MDM2 by RT-qPCR. Finally, we identified the differential metabolites (DMs), and found the metabolism profile was significantly regulated by siSHMT2. Besides the purine metabolism, we observed that valine, leucine and isoleucine biosynthesis and degradation, TCA cycle, and propanoate metabolism were among the top pathways of DMs.

Discussion: In summary, we highlight the important roles of SHMT2 in HT-1376 cells and identified its downstream molecular targets, which are associated with the development of BLCA and can be used as therapeutic targets of BLCA in future.

Background: Obstructive sleep apnea (OSA) and major depressive disorder (MDD) impose substantial quality-of-life burdens and socioeconomic costs. Growing evidence indicates bidirectional disease interactions that exacerbate clinical outcomes. This study identifies diagnostic biomarkers and explores therapeutic targets underlying OSA-MDD comorbidity.

Methods: We analyzed OSA/MDD-specific differentially expressed genes (DEGs) from Gene Expression Omnibus (GEO) datasets. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules. Protein-protein interaction (PPI) networks derived key genes via STRING. Diagnostic markers were established through dual-algorithm screening, with immune associations and therapeutic potential assessed. Finally, in vitro validation confirmed key findings.

Results: We identified 77 comorbid OSA-MDD DEGs. Integrated WGCNA-PPI analysis revealed eight key hub genes. LASSO regression nominated three diagnostic markers, including CD74 (CD74 molecule), RPL26L1 (ribosomal protein L26 like 1), and MRPL9 (mitochondrial ribosomal protein L9). MRPL9 was excluded for low diagnostic value for OSA and MDD. CD74 and RPL26L1 markers correlated with immune cell infiltration in OSA and MDD. In vitro, intermittent hypoxia significantly upregulated CD74 and RPL26L1 in microglia versus normoxia controls.

Conclusion: CD74 and RPL26L1 represent mechanistically grounded diagnostic biomarkers and therapeutic targets for OSA-MDD comorbidity. Shared pathways offer novel intervention opportunities for both conditions.