Genes最新文献

Background/Objectives: Consanguine families are helpful to identify recessive candidate genes for inherited diseases, but can also show an unusual inheritance pattern of pathogenic mutations. In this case series, we demonstrate this in five consanguine families with epilepsy from Pakistan. Methods: We performed whole exome sequencing of respective index patients, analyzed the data using two different models for inheritance of mutations and determined the segregation pattern of relevant mutations in the families by bi-directional Sanger sequencing. Results: Apart from mutations in classical dominant epilepsy genes (TSC2, DEPDC5, and CACNA1I), pathogenic mutations in rare recessive epilepsy-related genes (PGAP2, NOVA2, and CCDC88C) were also identified. Interestingly, we were able to provide evidence that GALR2 is potentially an additional gene associated with a recessive form of epilepsy. In one family, a homozygous 'pathogenic' TRAF3IP1 p. Gly387* nonsense mutation was identified, which, most probably due to stop-codon read-through, did not contribute to the phenotype. Conclusions: Our case series of consanguine families with epilepsy exemplifies the inheritance pattern of mutations in rare recessive epilepsy genes, and shows that mutations in classical epilepsy genes showing dominant or sporadic inheritance can also be relevant. That requires the analysis of whole exome data on the basis of different inheritance models.

Background: Cultivated strawberry (Fragaria × ananassa) is one of the most valuable horticultural crops worldwide. Nevertheless, its productivity is increasingly constrained by high susceptibility to adverse environmental conditions, which are intensified by climate change. Drought represents a major limitation, often accompanied by water deficiency and elevated soil salinity. Plants counteract such abiotic stresses through complex molecular defense mechanisms involving transcription factors that regulate stress-responsive gene expression.

Methods: In this study, we conducted a systematic bioinformatic analysis of the Tubby-like protein (TLP) transcription factor family in Fragaria × ananassa. RT-qPCR was used to analyze the expression patterns of FaTLP genes under different conditions to elucidate their potential roles in stress adaptation.

Results: Eight FaTLP genes were identified in each of the four subgenomes, most of which retained the characteristic TUBBY and F-box domains. Gene expression profiling revealed that several FaTLP genes were differentially expressed in leaves under drought and salt stress, with FaTLP2 and FaTLP7 exhibiting strong induction. In addition, the expression of FaTLP2 and FaTLP7 under various oxidative and signaling-related treatments, as well as in different tissues of strawberry plants were analyzed. Promoter analysis identified multiple cis-regulatory elements associated with phytohormone signaling and abiotic stress responses, such as ABRE, MYB, and MYC motifs. Phylogenetic analysis showed that FaTLP2 and FaTLP7 share high sequence similarity with orthologous TLPs from other plant species known for enhanced stress tolerance, suggesting that these proteins may play conserved roles in the molecular mechanisms underlying drought and salinity resilience.

Conclusions: This study provides valuable insights into the potential roles of FaTLPs in regulating environmental signal transduction and transcriptional control, contributing to abiotic stress tolerance in Fragaria × ananassa.

Background/objectives: The RNA-binding protein CELF1 is crucial for cardiac development, but its role in cardiomyocyte hypertrophy is unclear. This study investigates the effects of acute CELF1 knockdown on alternative splicing and hypertrophic growth in cardiomyocytes.

Methods: Neonatal rat cardiomyocytes (NRCMs) were transfected with two siRNAs targeting CELF1. Hypertrophy was assessed by cell size and expression of hypertrophic markers via qPCR and Western blot. RNA sequencing was performed in NRCMs to identify alternative splicing events. Tead1 function was tested by knockdown in NRCMs. Selected mechanistic assays were performed primarily in HeLa cells.

Results: CELF1 knockdown in NRCMs increased cardiomyocyte size and upregulated hypertrophic markers, while its overexpression restored the phenotype. RNA-seq revealed that CELF1 knockdown alters the alternative splicing pattern. Specifically, the splicing of the transcription factor Tead1 shifted from the full-length long Tead1 isoform (Tead1-L) to the exon 4-skipped short isoform (Tead1-S). In HeLa cells, CELF1 interacted with hnRNPC, an m⁶A reader and splicing factor, and CELF1 perturbation correlated with changes in global m⁶A abundance.

Conclusions: These findings suggest that CELF1 regulates hypertrophic phenotypes in cardiomyocytes and is associated with alternative splicing of Tead1.

Background/objectives: Angelman syndrome is a neurodevelopmental disorder resulting from a deficiency of the maternally inherited UBE3A gene. In mature neurons, UBE3A expression is restricted to the maternal allele due to tissue-specific genomic imprinting, while the paternal allele is silenced in cis by the UBE3A antisense transcript (UBE3A-ATS). To date, numerous strategies have been employed to activate paternal UBE3A expression. In this study, we utilized RNA interference (RNAi) to investigate the downregulation of UBE3A-ATS in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons.

Methods: To induce paternal UBE3A expression, we employed small interfering RNA (siRNA) oligonucleotides (20 mouse candidates and 47 human candidates) and lentiviral short hairpin RNA (LV-shRNA) targeting SNORD115 to suppress UBE3A-ATS expression in both mouse primary neurons and iPSCs. Subsequently, we assessed the expression levels of Angelman syndrome-related neighboring and target genes at the transcript and, where applicable, protein levels.

Results: Following treatment with siSnord115 or LV-shSnord115, we observed a reduction in Ube3a-ATS and a corresponding activation of paternal Ube3a RNA and protein expression in both Ube3a^P-YFP/m+ and Ube3a^p+/m- mouse primary neurons. A similar effect was observed upon treatment with LV-shSNORD115s in human iPSC-derived neurons.

Conclusions: shRNA-mediated inhibition of Ube3a-ATS by targeting Snord115 effectively restores Ube3a/UBE3A expression in both mouse neurons and human iPSCs. While promising, the mild reduction in Snord116 raises concerns about potential off-target effects. AAV-based delivery of shRNA shows potential, but its translational applicability remains to be evaluated in vivo.

Background/objectives: Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy is an extremely rare autosomal recessive disorder caused by inborn errors of immunity. It is due to a loss-of-function mutation in the AIRE autoimmune regulator gene. Its manifestations include autoimmunity affecting endocrine glands, in addition to non-endocrine manifestations including dental enamel hypoplasia, alopecia areata, hepatitis, and chronic mucocutaneous candidiasis. Globally, 10 cases per million are affected by this condition, with higher incidence in highly consanguineous populations. Here, we describe a novel AIRE gene mutation in a pediatric patient from Lebanon, along with the observed phenotype.

Method: A nine-year-old boy with history of craniosynostosis presented with jaundice. His past medical history was significant for recurrent oral thrush, keratoconjunctivitis, nail dystrophy, and alopecia. Upon presentation, he had jaundice, isolated splenomegaly, and severe failure to thrive. Laboratory tests showed transaminitis, cholestasis, and hypergammaglobulinemia. Abdominal ultrasound findings were suggestive of cirrhosis with compensated portal hypertension. The differential diagnosis included viral infection, inborn errors of metabolism, and autoimmune hepatitis.

Results: Exome sequencing identified a novel homozygous pathogenic variant in the AIRE gene, NM_000383.4: c.1066dup p.(Arg356Profs*16), confirming the diagnosis.

Conclusions: This study expands the genotypic and phenotypic spectrum of a rare inborn error of immunity in a child with chronic mucocutaneous candidiasis, enamel hypoplasia, and hepatitis.

Background/Objectives: MYH9 gene variants cause MYH9-related disease (MYH9-RD), which is also known as Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, and Sebastian syndrome. MYH9-RD is characterized by sensorineural hearing loss, macrothrombocytopenia, thrombocytopenia, hematuria/proteinuria, glomerulonephritis, cataracts purpura, and mucosal bleeding. In addition, the MYH9 gene is also known to be causative of autosomal dominant non-syndromic hearing loss (DFNA17). MYH9-RD is a relatively rare disorder, and the detailed clinical features and mutational spectra remain unclear. Methods: In this study, we performed next-generation sequencing analysis for 15,684 hearing loss patients and identified MYH9-associated hearing loss patients. Detailed clinical information was collected for these patients and summarized. Results: In this study, we identified 24 patients from 18 families with MYH9-associated hearing loss. We clarified the details of hearing deterioration observed in patients based on collected serial audiogram data. Some cases showed rapid hearing deterioration that worsened by about 50 dB within 5 years. Hearing loss is more likely to progress in patients with myosin head domain variants than in patients with myosin tail domain variants, but hearing loss in each set of patients finally deteriorates to bilateral profound hearing loss. Conclusions: In this study, we were able to clarify the detailed characteristics of MYH9-RD- and DFNA17-related hearing loss in a relatively large number of patients, particularly in some cases that showed rapid and asymmetrical hearing deterioration progressing to bilateral profound hearing loss. Our data will be useful for providing more appropriate treatment and follow-up for MYH9-associated hearing loss.

Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 70% of newly diagnosed bladder cancer cases but exhibits significant clinical heterogeneity in treatment response and progression risk. While intravesical bacillus Calmette-GuérinCa (BCG) therapy remains the gold standard for high-risk disease, approximately 30-50% of patients experience BCG failure, creating a critical decision point between additional bladder-sparing therapy (BST) and early radical cystectomy (RC). Recent clinical data from the CISTO study suggest that, in appropriately selected patients, RC may be associated with higher 12-month recurrence-free survival while maintaining comparable cancer-specific survival and physical functioning. In this narrative review, we synthesize contemporary evidence on NMIBC genomic and transcriptomic subtypes, immune contexture, and clinicopathologic features associated with BCG response and progression risk, with emphasis on clinically oriented classification systems such as BCG Response Subtypes (BRS1-3) and UROMOL21. We highlight how tumor-intrinsic biology (e.g., EMT-associated programs), immune phenotypes (inflamed vs. immune-cold microenvironments), and genomic alterations may help refine risk stratification beyond traditional clinicopathologic models. To facilitate clinical integration, we propose a conceptual decisional framework that combines molecular subtype assignment, immune profiling, key pathologic risk factors, and patient considerations to generate probabilistic risk tiers that support selection among early RC, BST, and clinical trial strategies. Standardized multicenter cohorts and prospective evaluation are needed to validate integrated models and define their clinical utility for the precision timing of cystectomy in BCG-unresponsive NMIBC.

Background: Physical activity (PA) and weight regulation are influenced by both genetic and lifestyle factors. This study aimed to evaluate the predictive value of Polygenic Risk Scores (PRSs) for PA and weight outcomes, and their interaction with dietary habits.

Methods: Baseline phenotypic data from 202 participants enrolled in the iMPROVE study were analyzed. The sample included 59 men and 143 women, aged 19-65 years. Based on baseline Body Mass Index (BMI), 75 participants were classified as having overweight and 126 as having obesity. Polygenic risk scores (PRSs) were calculated for 197 participants with available genetic data. PA was operationalized as metabolic equivalent of task minutes per week (MET-mins/week), derived from self-reported activity questionnaires. Weight-related outcomes included log-transformed weight loss from baseline to month 3 and change in BMI post-intervention. Interactions with diet were examined using both the randomized intervention dietary groups and previously extracted dietary patterns from the iMPROVE cohort. Correlation analyses and linear regression models were used to assess the main effects of PRSs and dietary patterns, as well as gene-diet interactions.

Results: The measured PA PGS002254 presented a nominal significant interaction with diet group for weight loss post-intervention (B = 7.57, SE = 3.57 × 10⁰, p = 0.04; R² = 0.06). Similarly, the sedentary behavior PGS001923 presented a significant interaction with the "High in unsaturated fats and fruit juice consumption" pattern for baseline MET-mins/week (B = 1.51 × 10³, SE = 4.135 × 10², p = 0.001; R² = 0.091).

Conclusions: Genetic predisposition influences short-term activity and weight outcomes, with dietary patterns moderating these effects. However, the multifactorial nature of lifestyle behaviors is being underscored by the modest variance explained.

Molecular sex determination in Syrian hamsters (Mesocricetus auratus) has been limited by the incomplete annotation of Y-linked loci in currently available genome assemblies. Here, we evaluate the Y-linked gene PRSSLY, which encodes a testis-specific serine protease-like protein, as a molecular marker for genetic sexing of Syrian hamster embryonic and placental tissues. Primers flanking a conserved PRSSLY coding region produced a male-specific amplicon showing 100% concordance with results from the established KDM5C/KDM5D PCR assay in E15.5 tail biopsies. SYBR Green-based qPCR enables the accurate detection of PRSSLY, characterized by a unique melt-curve profile, exclusively in male samples, allowing for efficient and sensitive mid-throughput analysis. Application of the PRSSLY assay to 417 placental samples from 39 dams demonstrated its suitability for large-scale sex genotyping, enabling sex assignment in the majority of samples despite the intrinsic complexity of placental tissue containing both maternal and embryonic genetic material. This assay provides a robust and reproducible approach for accurate sex genotyping in developmental and reproductive studies using Syrian hamsters.

Background/Objectives: The dopaminergic system regulates motivation, executive functions, motor learning, and emotional responses-processes that are key in both sport and esports. Although many studies analyse dopaminergic gene polymorphisms, their impact on psychophysical predispositions remains unclear. This narrative review aims to summarise current knowledge about the mechanisms of dopamine action and genetic determinants that may influence athletic and cognitive performance. Methods: The PubMed, Scopus, and Web of Science databases (publications from January 2010 to December 2025) were searched using keywords related to the DRD1-DRD5, COMT, SLC6A3/DAT1, and TH genes, as well as the terms 'sport' and 'esport.' Studies of athletes were included in which the relationship between dopaminergic polymorphisms and motivational and personality traits was assessed, and the results of neuroimaging and epigenetic studies were also considered. Results: Dopaminergic polymorphisms are associated with differences in reward processing, cognitive flexibility, motivation, and stress resilience. The most essential critical effects concern the DRD2 and DRD4 variants, which are associated with novelty seeking, reward dependence, and coping with stress. The COMT Val158Met polymorphism affects dopamine levels in the prefrontal cortex, modulating executive functions. The effects of individual polymorphisms are moderate, and conclusions regarding esports remain speculative due to limited research in this area. Conclusions: Dopaminergic predispositions involve interactions among genetics, neural activity, and the environment. However, current evidence is limited by small sample sizes, a predominance of European populations, scarce data on esports players, and difficulties in separating genetic effects from training-related adaptations.