Case report of a novel mutation in the TNC gene in Chinese patients with nonsyndromic hearing loss.

RATIONALE: Hereditary hearing loss is known to exhibit a significant degree of genetic heterogeneity. Herein, we present a case report of a novel mutation in the tenascin-C (TNC) gene in Chinese patients with nonsyndromic hearing loss (NSHL). PATIENT CONCERNS: This includes a young deaf couple and their 2-year-old baby. DIAGNOSES: Based on the clinical information, hearing test, metagenomic next-generation sequencing (mNGS), Sanger sequencing, protein function and structure analysis, and model prediction, in our case, the study results revealed 2 heterozygous mutations in the TNC gene (c.2852C>T, p.Thr951Ile) and the TBC1 domain family member 24 (TBC1D24) gene (c.1570C>T, p.Arg524Trp). These mutations may be responsible for the hearing loss observed in this family. Notably, the heterozygous mutations in the TNC gene (c.2852C>T, p.Thr951Ile) have not been previously reported in the literature. INTERVENTIONS: Avoid taking drugs that can cause deafness, wearing hearing AIDS, and cochlear implants. OUTCOMES: Regular follow-up of family members is ongoing. LESSONS: The genetic diagnosis of NSHL holds significant importance as it helps in making informed treatment decisions, providing prognostic information, and offering genetic counseling for the patient's family.

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.

Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B's ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.

Novel prognostic biomarker TBC1D1 is associated with immunotherapy resistance in gliomas.

Background: Glioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy. Methods: We identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves. Results: The levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas. Conclusion: Heightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. Blocking TBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.

Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.

Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.

The Ras GTPase-activating protein UvGap1 orchestrates conidiogenesis and pathogenesis in the rice false smut fungus Ustilaginoidea virens.

Ras GTPase-activating proteins (Ras GAPs) act as negative regulators for Ras proteins and are involved in various signalling processes that influence cellular functions. Here, the function of four Ras GAPs, UvGap1 to UvGap4, was identified and analysed in Ustilaginoidea virens, the causal agent of rice false smut disease. Disruption of UvGAP1 or UvGAP2 resulted in reduced mycelial growth and an increased percentage of larger or dumbbell-shaped conidia. Notably, the mutant ΔUvgap1 completely lost its pathogenicity. Compared to the wild-type strain, the mutants ΔUvgap1, ΔUvgap2 and ΔUvgap3 exhibited reduced tolerance to H2 O2 oxidative stress. In particular, the ΔUvgap1 mutant was barely able to grow on the H2 O2 plate, and UvGAP1 was found to influence the expression level of genes involved in reactive oxygen species synthesis and scavenging. The intracellular cAMP level in the ΔUvgap1 mutant was elevated, as UvGap1 plays an important role in maintaining the intracellular cAMP level by affecting the expression of phosphodiesterases, which are linked to cAMP degradation in U. virens. In a yeast two-hybrid assay, UvRas1 and UvRasGef (Ras guanyl nucleotide exchange factor) physically interacted with UvGap1. UvRas2 was identified as an interacting partner of UvGap1 through a bimolecular fluorescence complementation assay and affinity capture-mass spectrometry analysis. Taken together, these findings suggest that the UvGAP1-mediated Ras pathway is essential for the development and pathogenicity of U. virens.

SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle.

SARS-CoV-2, the causative agent of COVID-19, uses the host endolysosomal system for entry, replication, and egress. Previous studies have shown that the SARS-CoV-2 virulence factor ORF3a interacts with the lysosomal tethering factor HOPS complex and blocks HOPS-mediated late endosome and autophagosome fusion with lysosomes. Here, we report that SARS-CoV-2 infection leads to hyperactivation of the late endosomal and lysosomal small GTP-binding protein Rab7, which is dependent on ORF3a expression. We also observed Rab7 hyperactivation in naturally occurring ORF3a variants encoded by distinct SARS-CoV-2 variants. We found that ORF3a, in complex with Vps39, sequesters the Rab7 GAP TBC1D5 and displaces Rab7 from this complex. Thus, ORF3a disrupts the GTP hydrolysis cycle of Rab7, which is beneficial for viral production, whereas the Rab7 GDP-locked mutant strongly reduces viral replication. Hyperactivation of Rab7 in ORF3a-expressing cells impaired CI-M6PR retrieval from late endosomes to the trans-Golgi network, disrupting the biosynthetic transport of newly synthesized hydrolases to lysosomes. Furthermore, the tethering of the Rab7- and Arl8b-positive compartments was strikingly reduced upon ORF3a expression. As SARS-CoV-2 egress requires Arl8b, these findings suggest that ORF3a-mediated hyperactivation of Rab7 serves a multitude of functions, including blocking endolysosome formation, interrupting the transport of lysosomal hydrolases, and promoting viral egress.

Identification of new subtypes and potential genetic signatures in triple-negative breast cancer using weighted gene co-expression network analysis.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Here, we used gene expression profiling to define new subtypes of TNBC, which may improve prevention and treatment through personalized medicine. MATERIALS AND METHODS: Gene expression profiles from the public datasets GSE76250, GSE61724, GSE61723, and GES76275 were subjected to co-expression analysis to identify differentially expressed genes (DEGs) between TNBC and non-TNBC tissues. Consistency clustering was used to define TNBC subtypes, whose correlation with gene modules was analyzed. Enrichment analysis was used to identify module genes' biological functions and pathways. Single-sample gene set enrichment analysis was used to assess immune cell infiltration in the different TNBC subtypes, and the ChAMP package was used to examine methylation sites in TNBC. RESULTS: A total of 4,958 DEGs in TNBC were identified, which showed the same expression differences across all datasets as in the dataset GSE76250 and clustered into 9 co-expression modules. TNBC samples clustered into two subtypes based on nine hub genes from the modules. Class I showed the most significant correlation with module 1, whose genes were related mainly to interleukin-1 response, while class II showed the most significant correlation with module 6, whose genes were related mainly to the transforming growth factor-ß pathway. Class I was significantly enriched in cell cycle and DNA replication, and tumors of this subtype showed lower immune cell infiltration than class II tumors. Tumor infiltration by Th2 cells correlated positively with the expression of MCM10 and negatively with the expression of PREX2. A greater methylation of CIDEC, DLC1, EDNRB, EGR2 and SRPK1 correlated with better prognosis. CONCLUSIONS: Class I TNBC, for which a useful biomarker is MCM10, may be associated with a worse prognosis than class II TNBC, for which PREX2 may serve as a biomarker.

SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity.

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1-knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1-related neurodevelopmental disorders.

Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss.

Hearing loss is considered one of the most common sensory neurological defects, with approximately 60% of cases attributed to genetic factors. Human pathogenic variants in the TBC1D24 gene are associated with various clinical phenotypes, including dominant nonsyndromic hearing loss DFNA65, characterized by progressive hearing loss after the development of language. This study provides an in-depth analysis of the causative gene and mutations in a family with hereditary deafness. We recruited a three-generation family with autosomal dominant nonsyndromic hearing loss (ADNSHL) and conducted detailed medical histories and relevant examinations. Next-generation sequencing (NGS) was used to identify genetic variants in the proband, which were then validated using Sanger sequencing. Multiple computational software tools were employed to predict the impact of the variant on the function and structure of the TBC1D24 protein. A series of bioinformatics tools were applied to determine the conservation characteristics of the sequence, establish a three-dimensional structural model, and investigate changes in molecular dynamics. A detailed genotype and phenotype analysis were carried out. The family exhibited autosomal dominant, progressive, postlingual, and nonsyndromic sensorineural hearing loss. A novel heterozygous variant, c.1459C>T (p.His487Tyr), in the TBC1D24 gene was identified and confirmed to be associated with the hearing loss phenotype in this family. Conservation analysis revealed high conservation of the amino acid affected by this variant across different species. The mutant protein showed alterations in thermodynamic stability, elasticity, and conformational dynamics. Molecular dynamics simulations indicated changes in RMSD, RMSF, Rg, and SASA of the mutant structure. We computed the onset age of non-syndromic hearing loss associated with mutations in the TBC1D24 gene and identified variations in the hearing progression time and annual threshold deterioration across different frequencies. The identification of a new variant associated with rare autosomal dominant nonsyndromic hereditary hearing loss in this family broadens the range of mutations in the TBC1D24 gene. This variant has the potential to influence the interaction between the TLDc domain and TBC domain, thereby affecting the protein's biological function.

FilGAP controls cell-extracellular matrix adhesion and process formation of kidney podocytes.

The function of kidney podocytes is closely associated with actin cytoskeleton regulated by Rho small GTPases. Loss of actin-driven cell adhesions and processes is connected to podocyte dysfunction, proteinuria, and kidney diseases. FilGAP, a GTPase-activating protein for Rho small GTPase Rac1, is abundantly expressed in kidney podocytes, and its gene is linked to diseases in a family with focal segmental glomerulosclerosis. In this study, we have studied the role of FilGAP in podocytes in vitro. Depletion of FilGAP in cultured podocytes induced loss of actin stress fibers and increased Rac1 activity. Conversely, forced expression of FilGAP increased stress fiber formation whereas Rac1 activation significantly reduced its formation. FilGAP localizes at the focal adhesion (FA), an integrin-based protein complex closely associated with stress fibers, that mediates cell-extracellular matrix (ECM) adhesion, and FilGAP depletion decreased FA formation and impaired attachment to the ECM. Moreover, in unique podocyte cell cultures capable of inducing the formation of highly organized processes including major processes and foot process-like projections, FilGAP depletion or Rac1 activation decreased the formation of these processes. The reduction of FAs and process formations in FilGAP-depleted podocyte cells was rescued by inhibition of Rac1 or P21-activated kinase 1 (PAK1), a downstream effector of Rac1, and PAK1 activation inhibited their formations. Thus, FilGAP contributes to both cell-ECM adhesion and process formation of podocytes by suppressing Rac1/PAK1 signaling.

The high expression of TOP2A and MELK induces the occurrence of psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. However, the influence of the TOP2A and MELK genes on psoriasis remains unclear. METHODS: Psoriasis datasets GSE166388 and GSE181318 were downloaded from the Gene Expression Omnibus (GEO) database generated from GPL570 and GPL22120. Differential gene expression (DEGs) was identified. Functional enrichment analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and immune infiltration analysis were conducted. The protein-protein interaction (PPI) network was constructed and analyzed. Gene expression heat map was generated. The most relevant diseases associated with core genes were determined through comparison with the Comparative Toxicogenomics Database (CTD) website. TargetScan was used to select miRNAs regulating central DEGs. RESULTS: A total of 773 DEGs were identified. According to Gene Ontology (GO) analysis, they were mainly enriched in mitochondrial gene expression, oxidative phosphorylation, mitochondrial envelope, mitochondria and ribosome. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that target cells were mainly enriched in metabolic pathways, proteasome, and oxidative phosphorylation. Seven core genes (TOP2A, NUF2, MELK, ASPM, DLGAP5, CCNA2, DEPDC1B) were obtained. The gene expression heatmap showed high expression of core genes (TOP2A, MELK) in psoriasis samples, while DEPDC1B, CCNA2, DLGAP5, NUF2, ASPM were lowly expressed in psoriasis samples. CTD analysis found that TOP2A and MELK were related to skin neoplasms, skin diseases, psoriasis, erythema, dermatitis, and infections. CONCLUSION: TOP2A and MELK genes are highly expressed in psoriasis, and higher expression of TOP2A and MELK genes is associated with poorer prognosis.

RACGAP1 drives proliferation, migration and invasion and suppresses autophagy of gastric cancer cells via inhibiting SIRT1/Mfn2.

Objective: Gastric cancer is the most frequent gastrointestinal malignancy with a poor prognosis. Rac GTPase activation protein 1 (RACGAP1) is a novel tumor promotor, whose detailed effect on gastric cancer remains to be further elucidated. Hence, this study identifies the action of RACGAP1 on gastric cancer and investigates the potential mechanism. Methods: RACGAP1 expression in gastric cancer was analyzed based on the data of The Cancer Genome Atlas (TCGA) database. Cell proliferation was measured by CCK-8 and colony formation assay. Cell migration and invasion were evaluated by transwell assay. Cell apoptosis was assessed by flow cytometry. Cell autophagy was evaluated via determining LC3. Results: RACGAP1 presented at high level in gastric cancer cells. Overexpressed RACGAP1 potentiated gastric cancer cell proliferation, migration, and invasion. Besides, silenced RACGAP1 induced cell apoptosis and autophagy. Furthermore, RACGAP1 suppressed the expression of SIRT1 and Mfn2. Conclusion: RACGAP1 was overexpressed in gastric cancer. RACGAP1 potentiated aggressive behaviors of gastric cancer, and suppressed cell apoptosis and autophagy via modulating SIRT1/Mfn2. RACGAP1 may be a valuable target in the treatment of gastric cancer.

Genome-wide DNA methylation of lesional and peri-lesional skin in vitiligo: a comparative and integrated analysis of multi-omics in Chinese population.

Several studies have emphasized the role of DNA methylation in vitiligo. However, its profile in human skin of individuals with vitiligo remains unknown. Here, we aimed to study the DNA methylation profile of vitiligo using pairwise comparisons of lesions, peri-lesions, and healthy skin. We investigated DNA methylation levels in six lesional skin, six peri-lesional skin, and eight healthy skin samples using an Illumina 850 K methylation chip. We then integrated DNA methylation data with transcriptome data to identify differentially methylated and expressed genes (DMEGs) and analyzed their functional enrichment. Subsequently, we compared the methylation and transcriptome characteristics of all skin samples, and the related genes were further studied using scRNA-seq data. Finally, validation was performed using an external dataset. We observed more DNA hypomethylated sites in patients with vitiligo. Further integrated analysis identified 264 DMEGs that were mainly functionally enriched in cell division, pigmentation, circadian rhythm, fatty acid metabolism, peroxidase activity, synapse regulation, and extracellular matrix. In addition, in the peri-lesional skin, we found that methylation levels of 102 DMEGs differed prior to changes in their transcription levels and identified 16 key pre-DMEGs (ANLN, CDCA3, CENPA, DEPDC1, ECT2, DEPDC1B, HMMR, KIF18A, KIF18B, TTK, KIF23, DCT, EDNRB, MITF, OCA2, and TYRP1). Single-cell RNA analysis showed that these genes were associated with cycling keratinocytes and melanocytes. Further analysis of cellular communication indicated the involvement of the extracellular matrix. The expression of related genes was verified using an external dataset. To the best of our knowledge, this is the first study to report a comprehensive DNA methylation profile of clinical vitiligo and peri-lesional skin. These findings would contribute to future research on the pathogenesis of vitiligo and potential therapeutic strategies.

TBC1D1 represses glioma progression by altering the integrity of the cytoskeleton.

BACKGROUND: Glioma is one of the most aggressive malignant brain tumors and is characterized by invasive growth and poor prognosis. TBC1D1, a member of the TBC family, is associated with the development of various malignancies. However, the role of TBC1D1 in glioma-genesis remains unclear. METHODS: The effect of TBC1D1 on the prognosis of glioma patients and related influencing factors were analyzed in the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases. Expression of TBC1D1 in glioma cell lines was detected by western blotting. Cell viability and proliferation were measured by EdU and Colony formation assays, respectively. Transwell and wound healing assays were performed to determine the cell migration and invasion capacities. Immunofluorescence was used to observe actin morphology in the cytoskeleton. RESULTS: We discovered that high TBC1D1 expression in gliomas led to poor prognosis. Downregulation of TBC1D1 in glioma cells significantly inhibited multiple important functions, such as proliferation, migration, and invasion. We further demonstrated that the tumor-inhibitory effect of TBC1D1 might occur through the P-LIMK/cofilin pathway, destroying the cytoskeletal structure and affecting the depolymerization of F-actin, thereby inhibiting glioma migration. CONCLUSION: TBC1D1 affects the balance and integrity of the actin cytoskeleton via cofilin, thereby altering the morphology and aggressiveness of glioma cells. This study provides a new perspective on its role in tumorigenesis, thereby identifying a potential therapeutic target for the treatment of gliomas.

ARHGAP6 Suppresses Breast Cancer Tumor Growth by Promoting Ferroptosis via RhoA-ROCK1-p38 MAPK Signaling.

BACKGROUND: Ferroptosis, a distinct iron-dependent form of regulated cell death, is induced by severe lipid peroxidation due to reactive oxygen species (ROS) generation. Breast cancer patient survival is correlated with the tumor-suppressing properties of Rho guanosine triphosphatase hydrolase enzyme (GTPase)-activating protein 6 (ARHGAP6). This study investigates the impact and mechanisms of ARHGAP6 on ferroptosis in breast cancer. METHODS: Using quantitative RT-PCR, Western blotting, and immunofluorescence staining, ARHGAP6 expression was detected in a gene expression dataset, cancer tissue samples, and cells. ARHGAP6 was overexpressed or silenced in breast cancer cell lines. Cell proliferation was measured using 5-ethynyl-2-deoxyuridine (EdU) assay, and cell death rate was determined using LDH cytotoxicity assay. As indicators of ferroptosis, Fe2+ ion content, lipid ROS, glutathione peroxidase 4 (GPX4), ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1), prostaglandin-endoperoxide synthase 2 (PTGS2), solute carrier family 7 member 11 (SLC7A11), and acyl-CoA synthetase long chain family member 4 (ACSL4) levels were evaluated. RESULTS: ARHGAP6 was obviously downregulated in cancer tissues and cells. ARHGAP6 overexpression decreased cell proliferation, elevated cell death and lipid ROS, decreased GPX4 and SLC7A11, increased PTGS2, ACSL4, and CHAC1, and inhibited RhoA/ROCK1 and p38 MAPK signaling in cancer cells. ARHGAP6 knockdown exerted opposite effects to those of ARHGAP6 overexpression. p38 signaling suppression reversed the effect of ARHGAP6 knockdown on ferroptosis, while RhoA/ROCK1 signaling inhibition compromised the effect of ARHGAP6 on p38 MAPK signaling. In mice models, ARHGAP6 together with the ferroptosis inducer RSL3 cooperatively enhanced ferroptosis and inhibited tumor growth of cancer cells. ARHGAP6 mRNA level was positively correlated with that of ferroptosis indicators in tumor tissues. CONCLUSIONS: This study revealed that ARHGAP6 inhibited tumor growth of breast cancer by inducing ferroptosis via RhoA/ROCK1/p38 MAPK signaling. Integrating ARHGAP6 with ferroptosis-inducing agents may be a promising therapeutic strategy for breast cancer treatment.

ARHGAP18 is Upregulated by Transcription Factor GATA1 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma.

Rho GTPase activating protein 18 (ARHGAP18), a member of the RhoGAP gene family that increases GTP hydrolysis and inhibits RhoGTPase, was recently discovered to play a role in the development of breast cancer. However, its exact biological role in hepatocellular carcinoma (HCC) remains unclear. In our present study, we comprehensively assessed ARHGAP18 expression and its correlation with the prognostic value of cancer patients in databases. Cell proliferation and colony formation assays were employed to monitor cell growth. Luciferase reporter assay, Chromatin immunoprecipitation qPCR (ChIP-qPCR), immunofluorescence were performed for mechanism research. The expression of genes and proteins was detected by real-time PCR and western blotting. According to the findings of this research, ARHGAP18 protein levels are increased in HCC tissues compared to adjacent nontumor tissues, and ARHGAP18 overexpression is associated with poor survival. The results of a gain- and loss-of-function experiment with HCC cells in vitro demonstrated that ARHGAP18 stimulated cell proliferation, migration, and invasion. Mechanistically, we found that the transcription factor GATA binding protein 1 (GATA1) could bind to the ARHGAP18 promoter and facilitate ARHGAP18 expression. Further studies revealed that the effects of ARHGAP18 silencing on HCCLM3 and Bel-7402 cells were blocked by GATA1 overexpression. In conclusion, GATA1-mediated ARHGAP18 up-regulation plays an important role in HCC tumorigenesis and might be a potential therapeutic target for HCC.

Phenotypic and genotypic characterization of NPRL3-related epilepsy: Two case reports and literature review.

Nitrogen permease regulator-like 3 (NPRL3) has been reported to play a role in seizure onset. The principal manifestation of NPRL3-related epilepsy is a range of epilepsy-associated syndromes, such as familial focal epilepsy with variable foci (FFEVF), sleep-related hypermotor epilepsy (SHE), and temporal lobe epilepsy (TLE). The association between phenotype and genotype of NPRL3 mutations remains inadequately described. This study aimed to explore the phenotypic and genotypic spectra of NPRL3-related epilepsy. We reported two novel NPRL3 variants in two unrelated epilepsy cases, including a nonsense (c.1174C > T, p.Gln392*) and a missense variant (c.1322C > T, p.Thr441Met). Following a review of the literature, a total of 116 cases of NPRL3-related epilepsy were assessed, mostly with nonsense and frameshift mutations. Our findings suggest that patients harboring various NPRL3 variants exhibit variable clinical manifestations. In addition, it may be worthwhile to consider the existence of NPRL3 mutations in epilepsy patients with a family history. This study provides useful information for the treatment and prognosis by expanding the phenotypic and genotypic spectrum of NPRL3-related epilepsy. PLAIN LANGUAGE SUMMARY: This study expands the phenotypic and genotypic spectra of NPRL3-related epilepsy by reporting two cases with different novel variants. Following a review of the literature, it was observed that patients harboring various NPRL3 variants exhibited a variability of clinical manifestations. Also, patients carrying nonsense mutations are frequently prone to drug resistance and other severe comorbidities such as developmental delay, but more cases need to be collected to confirm these findings.

Seizure Control Outcomes following Resection of Cortical Dysplasia in Patients with DEPDC5 Variants: A Systematic Review and Individual Patient Data Analysis.

There is insufficient evidence regarding the efficacy of epilepsy surgery in patients with pharmacoresistant focal epilepsy and coexistent DEPDC5 (dishevelled EGL-10 and pleckstrin domain-containing protein 5) pathogenic (P), likely pathogenic (LP), or variance of unknown significance (VUS) variants. To conduct a systematic review on the literature regarding the use and efficacy of epilepsy surgery as an intervention for patients with DEPDC5 variants who have pharmacoresistant epilepsy. A systematic review of the current literature published regarding the outcomes of epilepsy surgery for patients with DEPDC5 variants was conducted. Demographics and individual patient data were recorded and analyzed. Subsequent statistical analysis was performed to assess significance of the findings. A total of eight articles comprising 44 DEPDC5 patients with genetic variants undergoing surgery were included in this study. The articles primarily originated in high-income countries (5/8, 62.5%). The average age of the subjects was 10.06 ± 9.41 years old at the time of study. The most common form of epilepsy surgery was focal resection (38/44, 86.4%). Thirty-seven of the 40 patients (37/40, 92.5%) with reported seizure frequency results had improvement. Twenty-nine out of 38 patients (29/38, 78.4%) undergoing focal resection achieved Engel Score I postoperatively, and two out of four patients achieved International League Against Epilepsy I (50%). Epilepsy surgery is effective in patients with pharmacoresistant focal epilepsy and coexistent DEPDC5 P, LP, or VUS variants.

Mapping the genetic architecture of idiopathic pulmonary fibrosis: Meta-analysis and epidemiological evidence of case-control studies.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare and devastating fibrotic lung disorder with unknown etiology. Although it is believed that genetic component is an important risk factor for IPF, a comprehensive understanding of its genetic landscape is lacking. Hence, we aimed to highlight the susceptibility genes and pathways implicated in IPF pathogenesis through a two-staged systematic literature search of genetic association studies on IPF, followed by meta-analysis and pathway enrichment analysis. METHODS: This study was performed based on PRISMA guidelines (PROSPERO, registration number: CRD42022297970). The first search was performed (using PubMed and Web of Science) retrieving a total of 5642 articles, of which 52 were eligible for inclusion in the first stage. The second search was performed (using PubMed, Web of Science and Scopus) for ten polymorphisms, identified from the first search, with 2 or more studies. Finally, seven polymorphisms, [rs35705950/MUC5B, rs2736100/TERT, rs2609255/FAM13A, rs2076295/DSP, rs12610495/DPP9, rs111521887/TOLLIP and rs1800470/TGF-ß1] qualified for meta-analyses. The epidemiological credibility was evaluated using Venice criteria. RESULTS: From the systematic review, 222 polymorphisms in 118 genes showed a significant association with IPF susceptibility. Meta-analyses findings revealed significant association of rs35705950/T [OR = 3.92(3.26-4.57)], rs2609255/G [OR = 1.50(1.18-1.82)], rs2076295/G [OR = 1.19(0.82-1.756)], rs12610495/G [OR = 1.28(1.12-1.44)], rs2736100/C [OR = 0.68(0.54-0.82), rs111521887/G [OR = 1.34(1.06-1.61)] and suggestive evidence for rs1800470/T [OR = 1.08(0.82-1.34)] with IPF susceptibility. Four polymorphisms- rs35705950/MUC5B, rs2736100/TERT, rs2076295/DSP and rs111521887/TOLLIP, exhibited substantial epidemiological evidence supporting their association with IPF risk. Gene ontology and pathway enrichment analysis performed on IPF risk-associated genes identified a critical role of genes in mucin production, immune response and inflammation, host defence, cell-cell adhesion and telomere maintenance. CONCLUSIONS: Our findings present the most prominent IPF-associated genetic risk variants involved in alveolar epithelial injuries (MUC5B, TERT, FAM13A, DSP, DPP9) and epithelial-mesenchymal transition (TOLLIP, TGF-ß1), providing genetic and biological insights into IPF pathogenesis. However, further experimental research and human studies with larger sample sizes, diverse ethnic representation, and rigorous design are warranted.