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    Pathogenic Ala303Val Mutation in the PROS1 Gene is Associated with the Pathogenesis of Deep Vein Thrombosis
    (Erciyes Univ Sch Medicine, 2022) Bali, Dilara Fatma Akin; Eroglu, Tamer; Ozkan, Didem Torun
    Objective: The aim of this study was to predict the functional impact of pathogenic mutations and the mRNA expression profiles of the platelet endothelial aggregation receptor 1 (PEAR1), protein S (alpha) (PROS1), and adrenoceptor alpha 2A (ADRA2A) genes in deep vein thrombosis (DVT), as well as to examine the effects of these genes on the pathogenesis of DVT. Materials and Methods: Patients diagnosed with DVT were selected for the study and healthy individuals were used as controls. Mutations in the PEAR1, PROS1, and ADRA2A genes were determined by DNA sequencing analysis and gene expressions were determined using quantitative real-time polymerase chain reaction testing. Polymorphism Phenotyping v2 (Polyphen-2: http://genetics.bwh.harvard.edu/pph2/), SNAP2 (https://rostlab.org/services/snap2web/) and MutationTaster (https://www.mutationtaster.org/) software were used to define the pathogenic effects of mutations detected by sequencing the selected genes in hotspot regions. Mutation and gene expression analyses were noted in the results and clinical data. Results: A total of 27 patients with DVT and 10 healthy individuals were included in the study. Twenty-one mutations were detected in the 27 patients, most often in the PROS1 gene. A p.Ala303Val mutation is located on the human sex hormone-binding globulin (SHBG) domain of mutation PROS1 and is pathogenic. A p.A303V mutation is associated with premature termination in codon 303 of the SHBG domain. Examination of the effect on the mRNA expression level of wild-type versus mutant genotypes revealed that the mutant PROS1 p.A303V expression was significantly lower (p=0.041). Conclusion: A p.A303V mutation in PROS1 might be an independent risk factor for DVT, which could provide helpful insight into the pathogenesis of DVT.
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    THE GENOMIC LANDSCAPE OF THE SWITCH/SUCROSE NON-FERMENTABLE CHROMATIN REMODELING COMPLEX IN ACUTE MYLEOID LEUKEMIA
    (2024) Ozkan, Didem Torun; Akın, Dilara Fatma
    The SWI/SNF chromatin remodeling complex is involved in the regulation of gene expression required for processes such as cell maintenance and differentiation in hematopoietic stem cells. Abnormalities in the SWI/SNF subunits involved in the homeostasis of hematologic processes contribute to the initiation or progression of hematologic malignancies, but the mechanisms underlying this phenotype are not yet fully understood. The aim of study is to comprehensively identify mutations and expression profiles in the genes forming the SWI/SNF complex using bioinformatics tools, with a focus on understanding the underlying mechanisms. Genomic sequences and expression profiles of an AML cohort (n:872) were obtained from using tools and subsequently analyzed. PolyPhen-2, SIFT, and Mutation Assessor tools were used to estimate the oncogenic/pathogenic effects of mutations identified in 9 genes encoding subunits of the complex ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCE1, SMARCB1, DPF2, PMBR1, and BCL7A in AML pathogenesis. STRING analysis was performed to better understand the functional relationships of the mutant proteins in cellular processes. Furthermore, to the mutation profile, gene expression and survival profiles were also determined. A total of 17 genetic abnormalities were determined in 9 genes, including 9 missense, 6 frameshift mutations, 1 mutation in the splice region, and 1 fusion mutation. In the AML cohort, the expression levels of ARID1A, ARID1B, SMARCA2, and PMBR1 were significantly higher in the patient group compared to the healthy group (p<0.01). Survival analysis based on low and high gene expression profiles showed no significant difference in results. In STRING analysis, our genes were found to have functional relationships with the PHF10 protein, which is involved in cell cycle control. The results suggest that the mutations identified in the ARID1A, ARID1B, SMARCA2, SMARCA4, and PBRM1 may disrupt the function of SWI/SNF chromatin remodeling complexes, possibly inducing/activating different cellular pathways involving different chromatin environments during AML pathogenesis.