Genes最新文献

Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the TSC1 and TSC2 tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1). Functional analysis of the effects of TSC1 and TSC2 variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to TSC1 and TSC2 in DNA isolated from 116 individuals with a definite clinical diagnosis of TSC. Missense variants and in-frame deletions were functionally assessed. Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2. Of these, 35 were novel. Disruption of TSC1/2 activity was demonstrated for seven TSC2 variants. Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis.

Background/objectives: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Key factors contributing to neuronal death include mitochondrial energy damage, oxidative stress, and excitotoxicity. The frontal cortex is crucial for action initiation, planning, and voluntary movements whereas the spinal cord facilitates communication with the brain, walking, and reflexes. By investigating transcriptome data from the frontal cortex and spinal cord, we aim to elucidate common pathological mechanisms and pathways involved in ALS for understanding the disease progression and identifying potential therapeutic targets.

Methods: In this study, we quantified gene and transcript expression patterns, predicted variants, and assessed their functional effects using computational tools. It also includes predicting variant-associated regulatory effects, constructing functional interaction networks, and performing a gene enrichment analysis.

Results: We found novel genes for the upregulation of immune response, and the downregulation of metabolic-related and defective degradation processes in both the spinal cord and frontal cortex. Additionally, we observed the dysregulation of histone regulation and blood pressure-related genes specifically in the frontal cortex.

Conclusions: These results highlight the distinct and shared molecular disruptions in ALS, emphasizing the critical roles of immune response and metabolic dysfunction in neuronal degeneration. Targeting these pathways may provide new therapeutic avenues to combat neurodegeneration and preserve neuronal health.

Background/Objectives: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors. Methods: Family members with a confirmed PEx diagnosis (one proband and two first-degree relatives) and non-affected members were recruited into this study. Exome sequencing was performed on all affected familial PEx cases to systematically screen for candidate genes that are likely to be causative for PEx, and on non-affected family members for variant segregation analysis. Results: Ten families, with three affected members each, participated, providing thirty familial PEx cases. Different inheritance patterns were represented across the ten pedigrees, with possible incomplete penetrance. Genetic variants in REST (essential for neuronal development and associated with pectus deformities in prior studies), SMAD4 (variants can predispose individuals to thoracic aortic diseases), and COL5A (associated with Ehlers-Danlos syndrome and Fibromuscular dysplasia) were initially identified as potentially linked to the development of pectus deformities and segregated with the phenotype. No variants were shared across families in the studied population. Conclusions: Germline exome sequencing of families with multiple individuals affected by PEx in our study identified potential gene candidates linked to PEx. These candidates are private to individual families and no strong candidates shared across multiple families were identified. These findings suggest that the inheritance of PEx may not be strongly related to a shared single genetic variant in known genes. Given the accumulating evidence for the genetic basis of familial PEx, further studies, including polygenic analyses, as well as assessment of the non-coding genome and possible epigenetic markers are warranted.

Background/Objectives: Homeobox (HOX) genes encode conserved transcription factors essential for tissue and organ development and cellular differentiation. In humans, these genes are organized into four clusters: HOXA, HOXB, HOXC, and HOXD. While HOX genes have been extensively studied in cancer biology, their roles in esophageal squamous cell carcinoma (ESCC) remain poorly understood. Given the increasing incidence and high mortality rate of ESCC, exploring the molecular drivers of this tumor is urgent. Methods: Therefore, this study investigated the mutational landscape and expression profiles of HOX genes in ESCC and their differentially expressed targets using ESCC data from The Cancer Genome Atlas (TCGA) and two independent transcriptome datasets. Results: We found that copy number alterations and single nucleotide variations were rare, while seven HOX genes (HOXA2, HOXA7, HOXB13, HOXC9, HOXC10, HOXC13, and HOXD10) were significantly differentially expressed in ESCC compared to paired non-malignant mucosa. Further analysis identified 776 potential HOX target genes differentially expressed in ESCC, many of which are involved in critical cancer pathways such as PI3K-AKT, cell cycle regulation, and epithelial-mesenchymal transition (EMT). The HOXA7 overexpression was associated with poor overall survival rates in ESCC. This finding opens new possibilities for targeted therapies, offering hope for improved patient outcomes. Conclusions: Thus, this study underscored the pivotal role of HOX gene dysregulation in ESCC and classified HOXA7 as a potential prognostic biomarker in this tumor.

Maize tassel spindle length is closely related to the number of pollen grains and the duration of the flowering stage, ultimately affecting maize yield and adaptations to stress conditions. In this study, 182 maize inbred lines were included in an association population. A genome-wide association study was conducted on maize tassel spindle length using the Q + K model. With p ≤ 1.0 × 10^-4 applied as the significance threshold, 240 SNPs significantly associated with tassel spindle length were detected, which were associated with 99 quantitative trait loci (QTLs), with 21 QTLs detected in two or more environments. Moreover, 51 candidate genes were detected in 21 co-localized QTLs. A KEGG enrichment analysis and candidate gene expression analysis indicated that Zm00001d042312 affects plant hormone signal transduction and is highly expressed in maize tassels. A haplotype analysis of Zm00001d042312 revealed three main haplotypes, with significant differences between Hap1 and Hap2. In conclusion, we propose that Zm00001d042312 is a gene that regulates maize tassel spindle length. This study has further elucidated the genetic basis of maize tassel spindle length, while also providing excellent genetic targets and germplasm resources for the genetic improvement of maize tassel spindle length and yield.

Background: The plant hormone cytokinin is a conserved regulator of plant development. LONELY GUY (LOG) proteins are pivotal in cytokinin biosynthesis. However, their origin, evolutionary history, and enzymatic characteristics remain largely uncharacterized.

Methods: To elucidate LOG family evolution history and protein motif composition, we conducted phylogenetic and motif analyses encompassing representative species across the whole green plant lineage. Catalytic activity and structure analysis were conducted to thoroughly characterize the LOG proteins.

Results: Our phylogeny showed that LOG proteins could be divided into five groups and revealed three major duplication events giving rise to four distinct groups of vascular LOG proteins. LOG proteins share a conserved structure characterized by a canonical motif arrangement comprising motifs 1, 2, 3, 4, 5, 6, and 7. Two significant changes in LOG motif composition occurred during the transition to land plants: the emergence of motif 3 in charophyte LOG sequences and the subsequent acquisition of motif 8 at the C-terminus of LOG proteins. Enzymatic assays demonstrated that LOG proteins can be classified into two groups based on their enzyme activity. One group act as cytokinin riboside 5'-monophosphate phosphoribohydrolase and primarily convert iPRMP to iP, while the other group act as 5'-ribonucleotide phosphohydrolase, and preferentially produce iPR from the same substrates. TaLOG5-4A1, TaLOG5-4A2, TaLOG5-5B2, and TaLOG5-D1 shared conserved residues in the critical motif and were predicted to have similar protein structures, but displayed distinct enzymatic activities.

Conclusions: Our findings provide a comprehensive overview of LOG protein phylogeny and lay a foundation for further investigations into their functional diversification.

Background: The screening of TERT promoter (TERTp) mutations is essential in cancer research and diagnostics, due to its prevalence in tumours associated with low self-renewal rates. TERTmonitor is a diagnosis kit primarily designed for real-time qPCR qualitative detection of -124C>T and -146C>T TERTp mutations, which are highly prevalent in several malignancies, particularly in bladder carcinoma.

Objective: This study aims to investigate TERTmonitor performance in droplet digital PCR (ddPCR) in urine samples from bladder cancer patients.

Methods: A total of 45 urine samples were examined by real-time qPCR and ddPCR techniques, and their performances were compared.

Results: TERTmonitor had similar performance in both real-time qPCR and ddPCR platforms. Specifically, the methods exhibited a concordance rate of 95.45% and 90% for -124C>T and -146C>T mutations, respectively. Importantly, an enhanced sensitivity in certain scenarios was exhibited by ddPCR when compared to real-time qPCR, detecting mutations that the latter failed to identify in approximately 4.55% and 10% of the samples for -124C>T and -146C>T mutations, respectively. This enhanced sensitivity of ddPCR was particularly evident in samples with low-frequency mutations.

Conclusions: The findings highlight the usefulness of TERTmonitor for cancer surveillance either in real-time qPCR or ddPCR platforms.

Background: Astilbe, consisting of about 18 species, is distributed throughout East Asia and Northeastern America, and most Astilbe species are widely cultivated as ornamental plants. A total of four species of Astilbe have been confirmed to be distributed throughout Korea, two of which are endemic to Korea.

Methods: In this study, we sequenced and assembled the complete chloroplast genomes of two endemic Korean plants using Illumina sequencing technology, identified simple sequence repeats (SSRs) and repetitive sequences, and compared them with three previously reported chloroplast genomes.

Results: The chloroplast genomes of the two species were 156,968 and 57,142 bp in length and had a four-part circular structure. They consisted of a large single-copy region of 87,223 and 87,272 bp and a small single-copy region of 18,167 and 18,138 bp, separated by a pair of inverted repeats (IRa and IRb, 25,789 and 25,866 bp). The genomes contained 130 genes, 49 SSRs, and 49 long repetitive sequences. Comparative analysis with the chloroplast genomes of five Astilbe species indicated that A. uljinensis was closely related to A. chinensis and A. taquetii to A. koreana.

Conclusions: This study provides valuable references for the identification of two endemic Korean Astilbe species and contributes to a deeper understanding of the phylogeny and evolution of the genus Astilbe.

Background/Objectives: The current research work aimed to evaluate the cryptic walnut genotypes of the Hazara region in Pakistan by using DNA barcoding and phylogenetic analysis. Methods: Based on morphological traits such as nut size, nut shape, and the number of leaflets, five genotypes were chosen and samples were collected for the current study. For molecular analysis, gDNA was isolated from the fresh leaves, and the five most effective angiosperm-specific markers, ITS2, rbcLa, rbcLc, rpoC1, and UBE3, were utilized. Based on amplification, sequencing, and identification success rates, ITS2 and UBE3 were recorded as the most efficient markers followed by rbcLa, rbcLc, and rpoC1. Results: During phylogenetic analysis, the query genotype-1 based on ITS2 and genotype-2 based on UBE3 clustered with (KF454101.1-Juglans regia) and (KC870919.1-J. regia) with bootstraps of 56 and 100, respectively. Genotype-3 based on rbcla clustered in a major clade with J. regia L., cultivars (MN397935.1 J. regia 'Vina') and (MN397934.1-J. regia 'Serr'), (MN397933.1 J. regia 'Pedro'), (MN397932.1 J. regia 'Lara'), (MN397931.1 J. regia 'Howard'), and (MN397930.1 J. regia 'Hartley') with bootstrap of 100. Meanwhile, genotype-4 and genotype-5 based on rbclc and rpoC1 clustered with (MN397935.1 J. regia 'Vina') and (MN397934.1 J. regia 'Serr'), across the database sequences. To clarify the taxonomic status of cryptic walnut genotypes, it is necessary to combine diverse DNA barcodes. The results of ITS2 and UBE3, followed by rbcL barcoding markers, are promising taxonomic tools for cryptic walnut genotypes in Pakistan. Conclusions: It has been determined that the genotypes of walnuts in the study area are both J. regia L. and its cultivars and that the accuracy of discrimination regarding the genus Juglans L. is greater than 90%. The reported DNA barcodes are recommended for the correct identification and genetic evaluation of Juglans taxa and its population.

Background: Ulcerative colitis is a chronic inflammatory disease affecting the colon. During chronic inflammation of epithelial cells, lipid metabolism via pro-inflammatory eicosanoids is known to modify the immune response.

Methods: Starting from the Mammalian Metabolic Database, the expression of metabolic enzymes was investigated in two independent cohorts from transcriptome datasets GSE38713 and GSE11223, which analyzed ulcerative colitis tissue samples from the digestive tract.

Results: In the first cohort, 145 differentially expressed enzymes were identified as significantly regulated between ulcerative colitis tissues and normal controls. Overexpressed enzymes were selected to tune an Elastic Net model in the second cohort. Using the best parameters, the model achieved a prediction accuracy for ulcerative colitis with an area under the curve (AUC) of 0.79. Twenty-two metabolic enzymes were found to be commonly overexpressed in both independent cohorts, with decreasing Elastic Net predictive coefficients as follows: LIPG (3.98), PSAT1 (3.69), PGM3 (2.74), CD38 (2.28), BLVRA (1.99), CBR3 (1.94), NT5DC2 (1.76), PHGDH (1.71), GPX7 (1.58), CASP1 (1.56), ASRGL1 (1.4), SOD3 (1.25), CHST2 (0.965), CHST11 (0.95), KYNU (0.94), PLAG2G7 (0.92), SRM (0.87), PTGS2 (0.80), LPIN1 (0.47), ME1 (0.31), PTGDS (0.14), and ADA (0.13). Functional enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database highlighted the main implications of these enzymes in cysteine and methionine metabolism (adjusted p-value = 0.01), arachidonic acid and prostaglandin metabolism (adjusted p-value = 0.01), and carbon metabolism (adjusted p-value = 0.04). A metabolic score based on the transcriptional activation of the validated twenty-two enzymes was found to be significantly greater in Ulcerative colitis samples compared to healthy donor samples (p-value = 1.52 × 10^-8).

Conclusions: A metabolic expression score was established and reflects the implications of heterogeneous metabolic pathway deregulations in the digestive tract of patients with ulcerative colitis.