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Comprehensive in-silico analysis of damage associated SNPs in hOCT1 affecting Imatinib response in chronic myeloid leukemia
Genomics ( IF 3.4 ) Pub Date : 2020-10-16 , DOI: 10.1016/j.ygeno.2020.10.007
Ismael Soltani 1 , Wael Bahia 2 , Assala Radhouani 3 , Abdelkarim Mahdhi 4 , Salima Ferchichi 2 , Wassim Y Almawi 5
Affiliation  

Non-synonymous single nucleotide polymorphisms (nsSNPs) in hOCT1 (encoded by SLC22A1 gene) are expected to affect Imatinib uptake in chronic myeloid leukemia (CML). In this study, sequence homology-based genetic analysis of a set of 270 coding SNPs identified 18 nsSNPs to be putatively damaging/deleterious using eight different algorithms. Subsequently, based on conservation of amino acid residues, stability analysis, posttranscriptional modifications, and solvent accessibility analysis, the possible structural-functional relationship was established for high-confidence nsSNPs. Furthermore, based on the modeling results, some dissimilarities of mutant type amino acids from wild-type amino acids such as size, charge, interaction and hydrophobicity were revealed. Three highly deleterious mutations consisting of P283L, G401S and R402G in SLC22A1 gene that may alter the protein structure, function and stability were identified. These results provide a filtered data to explore the effect of uncharacterized nsSNP and find their association with Imatinib resistance in CML.



中文翻译:

对影响慢性粒细胞白血病伊马替尼反应的 hOCT1 中损伤相关 SNP 的综合计算机分析

hOCT1 中的非同义单核苷酸多态性 (nsSNP)(由SLC22A1编码)基因)预计会影响慢性粒细胞白血病(CML)中伊马替尼的摄取。在这项研究中,基于序列同源性的一组 270 个编码 SNP 的遗传分析使用八种不同的算法确定了 18 个 nsSNP 被认为具有破坏性/有害性。随后,基于氨基酸残基的保守性、稳定性分析、转录后修饰和溶剂可及性分析,为高置信度的 nsSNP 建立了可能的结构-功能关系。此外,基于建模结果,揭示了突变型氨基酸与野生型氨基酸的一些不同之处,例如大小、电荷、相互作用和疏水性。SLC22A1中由P283L、G401S和R402G组成的三个高度有害的突变鉴定了可能改变蛋白质结构、功能和稳定性的基因。这些结果提供了过滤数据以探索未表征的 nsSNP 的影响,并发现它们与 CML 中伊马替尼耐药性的关联。

更新日期:2020-10-17
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