Frontiers in Genetics最新文献

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare monogenic kidney disorder characterized by progressive tubular atrophy and interstitial fibrosis. It is primarily associated with pathogenic variants in genes such as UMOD (uromodulin), REN (renin), MUC1 (mucin 1), and HNF1B (hepatocyte nuclear factor 1-beta). We report a unique Chinese case of ADTKD-UMOD in a patient carrying a UMOD gene mutation. The clinical presentation was complex: in addition to the classic features of UMOD mutations (hyperuricemia and gout), the patient exhibited endocrine and metabolic abnormalities typically linked to REN gene defects (ADTKD-REN), including anemia, hypotension, and hyporeninemic hypoaldosteronism. However, renal biopsy and genetic testing ultimately confirmed the diagnosis as ADTKD caused by a heterozygous missense mutation in UMOD gene.

Objective: To explore a novel combination of methylation markers for the differential diagnosis of malignant ascites (MA).

Materials and methods: A cohort of 164 cancer patients and 20 patients with benign disease presenting with ascites was enrolled. Ascites was tested by means of cytopathological routine diagnosis and DNA methylation detection of SHOX2, RASSF1A, SEPTIN9 and HOXA9 in the cytological specimens. DNA methylation in bisulfite-converted DNA was determined using semi-quantitative methylation-specific real-time PCR (MS-PCR). In addition, Kaplan-Meier method was used to plot the Overall survival (OS) curve based on the methylation status of four genes to explore the relationship between gene methylation status and prognosis of patients with ascites. The Cox regression model was used to analyze the survival factors.

Results: Methy-All-In-One Kit (OncoMe), a novel combination of SHOX2, RASSF1A, SEPTIN9 and HOXA9 methylation, led to an additional 29.9% increase in the detection rate of MA combined with the cytopathological test, resulting in a sensitivity of 76.2%. OncoMe showed high positive detection rates in Breast Cancer (87.5%), Pancreatic Cancer (83.3%), Gastric Cancer (79.5%), Cholangiocarcinoma (72.7%) and Ovarian Cancer (68.3%). Patients in the SHOX2 and SEPTIN9 methylation-positive groups had a significantly higher risk of disease progression than those in the negative groups. The OS of SHOX2 and SEPTIN9 gene methylation test negative group was higher than that of positive group.

Conclusion: OncoMe has potential for use as a biomarker for the detection of MA. Cytological examination combined with methylation detection can greatly improve the diagnosis rate of malignant ascites. The methylation status of SHOX2 and SEPTIN9 genes is significantly correlated with the prognosis of patients with ascites.

Introduction: Motile ciliopathies represent a group of disorders caused by impaired motility of cilia and flagella, resulting in clinical manifestations such as laterality defects, asthenospermia, chronic respiratory infections, and hydrocephalus. Although nearly 53 genes have been implicated, the genetic etiology remains unresolved in approximately 30% of cases, and the regulatory mechanisms of motile ciliogenesis are still incompletely understood.

Methods: Whole-exome sequencing was employed in a patient with laterality defects and recurrent pulmonary infections. Nasal epithelial brushings underwent high-speed video microscopy (HSVM) to evaluate ciliary beat pattern, and conventional transmission electron microscopy (TEM) to assess ultrastructure. CRISPR/Cas9 technology was harnessed to generate precise Lrrc56 knockout mice. Quantitative proteomics was conducted on Lrrc56-deficient compared with wild-type tissues to explore the mechanisms.

Results: Whole exome sequencing identified a novel homozygous frameshift variant in LRRC56 (c.148delG, p. Val50Trpfs*22) in the proband. HSVM of nasal cilia from the proband demonstrated severely dyskinetic motion, despite the absence of obvious ultrastructural defects on conventional TEM. Lrrc56-knockout mice recapitulated the patient's laterality defects and also exhibited additional phenotypes consistent with motile ciliopathies, including male infertility, hydrocephalus, and defective mucociliary clearance. Quantitative proteomic analysis revealed markedly reduced expression of cilia-associated proteins, particularly microtubule inner proteins (MIPs) and axonemal dynein assembly factors, in Lrrc56-deficient tissues compared with wild-type controls.

Discussion: Our findings establish LRRC56 as an essential regulator of ciliary motility and highlight its role in the pathogenesis of motile ciliopathies.

$K_s$ distribution, the distribution of the synonymous substitutions, has been widely used to estimate the species divergence using orthologous genes. However, conventional approaches often ignore the underlying bias that species divergence is delayed to average gene divergence by 2N _e generations, where N _e represents the ancestral effective population size, due to the lack of scalable methods for N _e inference. Here, we demonstrate through simulations that K _s distribution variance correlates with N _e, enabling direct estimation of ancestral population parameters from standard K _s data. Leveraging this relationship, we present Tspecies, a framework that corrects divergence time estimates using only substitution rates and K _s distributions, without requiring additional genomic data. Our practical application of Tspecies in Liriodendron has inferred a divergence time between North American and East Asian lineages (1.44 Ma) that align with early Pleistocene glaciation, and a large ancestral N _e (∼5.29 × 10⁴) consistent with fossil evidence. Our finding reveals the correlation between the variance of K _s distribution and N _e, and develops a computational framework to resolve the bias in K _s based dating by incorporating a readily estimated N _e.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, inherited immune-dysregulation syndrome that can present in the neonatal period and progress rapidly without timely recognition. We report a full-term female who developed abdominal distension, fever, hepatosplenomegaly, and coagulopathy within hours of birth, with multiorgan failure leading to death on day 5 despite intensive care and broad antimicrobial coverage. This timing, essentially at birth with death on day 5, is exceptionally rare in FHL2 and clinically instructive for sepsis-like neonatal presentations. Postmortem whole-exome sequencing identified compound heterozygous PRF1 variants, c.1131C>A (p.Cys377Ter) and c.65delC (p.Pro22Argfs*29), confirming FHL type 2. The presentation closely mimicked culture-negative neonatal sepsis, underscoring the diagnostic challenge of distinguishing primary HLH from infectious and metabolic conditions in early life. This case highlights the need for early clinical suspicion and rapid genomic testing in neonates with fulminant, sepsis-like inflammation. While HLH-directed therapy followed by hematopoietic stem-cell transplantation remains the standard pathway to improve survival, the fulminant neonatal course can outpace therapeutic windows, emphasizing the value of streamlined access to urgent genetics and specialist input.

Osteoarthritis (OA) is a common chronic degenerative joint disease. Chondrocytes undergo dynamic changes during the pathogenesis of OA, and the destruction of the extracellular matrix (ECM) and its homeostatic disruption are hallmarks of OA. This study explores the roles of transcriptional and alternative splicing (AS) mechanisms in regulating extracellular matrix (ECM) homeostasis in osteoarthritis (OA), using bulk and single-cell RNA-sequencing data. By analyzing two OA transcriptome datasets, we identified differentially expressed genes (DEGs) that are enriched in ECM-related pathways and constructed a regulatory network between differentially expressed transcription factors (DE TFs) and ECM-related DEGs. This revealed the potential roles of transcription factors ELF3 and DDIT3 in regulating the expression of COL3A1, COL5A2, and S100A4. Single-cell RNA-sequencing data further validated the expression patterns of ELF3 and DDIT3 in distinct chondrocyte subtypes. Additionally, by analyzing AS events, we identified the RNA-binding protein (RBP) KHDRBS3 as a regulator of AS for the ECM-related gene IL16. Aberrant changes in these events may impact the ECM environment of chondrocytes and contribute to the pathogenesis of OA. This study, for the first time, dissects the regulatory models in OA cartilage at both transcriptional and post-transcriptional levels. These findings provide novel potential targets for early diagnosis and intervention strategies in OA.

Background: Heart failure (HF) is the final stage of cardiovascular diseases. Nicotinamide metabolism (NMN) plays a key role in cardiovascular dysfunction. We aimed to explore genes correlated with NM pathway activity (NMRGs) in HF.

Methods: HF data were obtained from public databases, and NMRGs were sourced from literature. Weighted gene co-expression network analysis (WGCNA) identified NM-associated module genes. Candidate genes were selected via differential expression profiling and module analysis. Biomarkers were identified using protein-protein interaction (PPI) networks, machine learning, and gene expression validation. Diagnostic efficacy was assessed via nomogram. Functional enrichment, immune infiltration, and drug prediction analyses were performed. Biomarker expression was validated by Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR).

Results: Among 492 candidate genes, NDC1, NUP133, and TRMT11 were validated as biomarkers. The nomogram showed high diagnostic accuracy. Biomarkers were enriched in spliceosome and ubiquitin-mediated proteolysis pathways. Immune infiltration revealed correlations with neutrophils. Potential drugs, including tetradecanoylphorbol acetate, were identified. Biomarker expression was significantly lower in HF.

Conclusion: NDC1, NUP133, and TRMT11 are NM-related biomarkers in HF, offering insights into HF pathogenesis and therapy.

Almost half the mammalian genomes consist of transposable elements (TEs) and their derivatives. The distribution density of TEs can be associated with genomic regions of chromosomal rearrangements in different mammalian species and with the genomic localization of protein-coding genes that differ in length and function. To evaluate these characteristics at the local genomic level, an analysis of the distribution of various TEs (retrotransposons and DNA transposons) was performed in three mammalian species (human, cattle, and domestic rabbit) in genes with different functions and chromosomal localizations and their flanking regions. In humans and rabbits, melanophilin (MLPH) and myostatin (MSTN) are syntenic, but not in cattle. In the latter, MLPH and the leptin receptor (LEPR) are syntenic, but not in humans and rabbits. The alpha-thalassemia gene is always located on chromosome X. The results indicate that the frequencies of different TEs are species-specific and do not depend on the length of genes, their function, or chromosomal localization. There were also species-specific differences in the ratio of "ancient" and "young" short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs). There was a statistically significant positive correlation between ancient SINE + LINE and LTR-ERV (p < 0.01) and a significant negative correlation between young SINE + LINE and DNA transposons (p < 0.05). Competitive relationships between TEs are probably defined by the presence of identical regulatory motifs in different TEs, associated with the reliance of TE amplification on the host's own regulatory systems.