Farrokhi Shima, Eslahi Atieh, Alizadeh Farzaneh, Farshchian Zahra, Yousefi Yasamin, Mojarrad Majid
Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Heliyon. 2024 Aug 20;10(20):e36560. doi: 10.1016/j.heliyon.2024.e36560. eCollection 2024 Oct 30.
HLD17 (Hypomyelinating Leukodystrophy 17) is an inherited white matter disorder characterized by insufficient myelin production due to biallelic loss of function mutations in the aminoacyl-tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) gene. In silico analysis of SNVs (single nucleotide variants) in the AIMP2 gene is an efficient and cost-effective method for analyzing and predicting the impact of mutations on protein function and disease pathophysiology. The study used dbSNP and Ensembl databases to obtain data on 343 nonsynonymous single nucleotide variants (nsSNVs) in the human AIMP2 gene. Six prediction algorithm tools were used to assess the effects of these nsSNVs on AIMP2's functions and structures. Results showed that 18 nsSNVs were located within functional domains, while 10 nsSNVs led to decreased protein stability. The structural and functional properties of the AIMP2 protein were investigated using databases such as Predict Protein, Mutpred2, and HOPE. ConSurf analysis provided information about conserved nsSNVs. GeneMANIA and STRING software tools were used to predict interactions between gene-gene and protein-protein, respectively. Phyre2 and I-TASSER web servers were used to predict the 3D structures of wild-type and mutant proteins. In addition, having the challenge of probable post-translational modification sites in the AIMP2, we made predictions using various bioinformatics tools. Consecuently, three minor mutations (L138Q, V161E, and I188N) and five major mutations (C23S, D121G, I122S, P128S, and W268S) were found to affect the AIMP2 protein's structure or function. Anyway, These mutations need to be further studied and confirmed through experimental investigation and GWAS studies.
HLD17（低髓鞘性脑白质营养不良17型）是一种遗传性白质疾病，其特征是由于氨酰-tRNA合成酶复合物相互作用多功能蛋白2（AIMP2）基因的双等位基因功能丧失突变导致髓鞘生成不足。对AIMP2基因中的单核苷酸变异（SNV）进行计算机分析是一种分析和预测突变对蛋白质功能和疾病病理生理学影响的有效且经济高效的方法。该研究使用dbSNP和Ensembl数据库获取人类AIMP2基因中343个非同义单核苷酸变异（nsSNV）的数据。使用六种预测算法工具评估这些nsSNV对AIMP2功能和结构的影响。结果表明，18个nsSNV位于功能域内，而10个nsSNV导致蛋白质稳定性降低。使用Predict Protein、Mutpred2和HOPE等数据库研究了AIMP2蛋白的结构和功能特性。ConSurf分析提供了有关保守nsSNV的信息。分别使用GeneMANIA和STRING软件工具预测基因-基因和蛋白质-蛋白质之间的相互作用。使用Phyre2和I-TASSER网络服务器预测野生型和突变型蛋白质的三维结构。此外，由于AIMP2中可能存在翻译后修饰位点的挑战，我们使用各种生物信息学工具进行了预测。结果发现，三个小突变（L138Q、V161E和I188N）和五个大突变（C23S、D121G、I122S、P128S和W268S）会影响AIMP2蛋白的结构或功能。无论如何，这些突变需要通过实验研究和全基因组关联研究（GWAS）进行进一步研究和确认。
