Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative fatal disease that can affect the neurons of brain and spinal cord. ALS genetics has identified various genes to be associated with disease pathology. Oxidative stress induced bunina and lewy bodies formation can be regulated through the action of SOD1 protein. Hence, in the present study we aim to analyse the structural and functional annotation of various reported SOD1 variants throughout and their putative correlation with the location of mutation and degree of ALS severity by inferring the structural and functional alterations in different SOD1 variants. Methods We have retrieved around 69 SNPs of SOD1 gene from Genecards . Structural annotation of SOD1 variants were performed using SWISS Model, I - Mutant 2.0, Dynamut, ConSurf . Similarly, the functional annotation of same variants were done using SIFT, PHP - SNP , PolyPhen2, PROVEAN and RegulomeDB . Ramachandran plot was also obtained for six synonymous SNPs to compare the amino acid distribution of wild-type SOD1 (WT SOD1) protein. Frequency analysis, Chi square analysis, ANOVA and multiple regression analysis were performed to compare the structural and functional components among various groups. Results and conclusion Results showed the mutations in conserved domain of SOD1 protein are more deleterious and significantly distort the tertiary structure of protein by altering Gibb’s free energy and entropy. Moreover, significant changes in SIFT, PHP-SNP, PolyPhen2, PROVEAN and RegulomeDB scores were also observed in mutations located in conserved domain of SOD1 protein. Multiple regression results were also suggesting the significant alterations in free energy and entropy for conserved domain mutations which were concordant with structural changes of SOD1 protein. Results of the study are suggesting the biological importance of location of mutation(s) which may derive the different disease phenotypes and must be dealt accordingly to provide precise therapy for ALS patients.

中文翻译：

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保守结构域 SOD1 突变对 ALS 严重程度和治疗结果有任何作用吗？

背景 肌萎缩侧索硬化 (ALS) 是一种进行性神经退行性致命疾病，可影响大脑和脊髓的神经元。ALS 遗传学已经确定了与疾病病理学相关的各种基因。氧化应激诱导的 bunina 和路易体形成可以通过 SOD1 蛋白的作用进行调节。因此，在本研究中，我们旨在通过推断不同 SOD1 变体的结构和功能改变来分析各种报告的 SOD1 变体的结构和功能注释，以及它们与突变位置和 ALS 严重程度的假定相关性。方法 我们从Genecards 中检索到了大约69 个SOD1 基因的SNP。使用 SWISS Model、I-Mutant 2.0、Dynamut、ConSurf 对 SOD1 变体进行结构注释。相似地，相同变体的功能注释是使用 SIFT、PHP-SNP、PolyPhen2、PROVEAN 和 RegulomeDB 完成的。还获得了六个同义 SNP 的 Ramachandran 图，以比较野生型 SOD1 (WT SOD1) 蛋白的氨基酸分布。进行频率分析、卡方分析、方差分析和多元回归分析以比较各组之间的结构和功能成分。结果与结论结果表明SOD1蛋白保守结构域的突变更有害，通过改变Gibb自由能和熵显着扭曲蛋白质的三级结构。此外，在位于 SOD1 蛋白保守域的突变中也观察到 SIFT、PHP-SNP、PolyPhen2、PROVEAN 和 RegulomeDB 评分的显着变化。多元回归结果还表明保守结构域突变的自由能和熵发生了显着变化，这与 SOD1 蛋白的结构变化一致。该研究的结果表明突变位置的生物学重要性，这些突变可能导致不同的疾病表型，必须相应地处理，以便为 ALS 患者提供精确的治疗。