Department of Bioinformatics & Biotechnology, International Islamic University (IIUI), Islamabad, Pakistan.
PMAS Arid Agriculture University, Rawalpindi, Pakistan.
J Biomol Struct Dyn. 2022;40(23):12660-12673. doi: 10.1080/07391102.2021.1975561. Epub 2021 Sep 23.
This study conducted an in-depth analysis combining computational and experimental verifications of the deleterious missense mutations associated with the SLC29A4 protein. The functional annotation of the non-synonymous single nucleotide polymorphism (nsSNPs), followed by structure-function analysis, revealed 13 single nucleotide polymorphisms (SNP) as the most damaging. Among these, six mutants P429T/S, L144S, M108V, N86H, and V79E, were predicted as structurally and functionally damaging by protein stability analysis. Also, these variants are located at evolutionary conserved regions, either buried, contributing to the structural damage, or exposed, causing functional changes in the protein. These mutants were further taken for molecular docking studies. When verified via experimental analysis, the SNPs M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) showed an association with type 2 diabetes mellitus (T2DM). Minor allele frequency for rs149798710 (A > G) was 0.23 in controls, 0.29 in metformin responders, 0.37 in metformin non-responder, for rs151039853 (A > C) was 0.21 in controls, 0.28 in metformin responders, 0.36 in metformin non-responder and for rs17854505 (T > A) was 0.20 in controls, 0.25 in metformin responders, 0.37 in metformin non-responder. Hence, this study concludes that SLC29A4 M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) polymorphisms were associated with the increased risk of T2DM as well as with the increased risk towards the failure of metformin therapeutic response in T2DM patients of Pakistan. Communicated by Ramaswamy H. Sarma.
本研究通过计算和实验验证相结合，深入分析了与 SLC29A4 蛋白相关的有害错义突变。对非同义单核苷酸多态性（nsSNP）进行功能注释，然后进行结构-功能分析，结果显示 13 个单核苷酸多态性（SNP）的破坏性最大。其中，P429T/S、L144S、M108V、N86H 和 V79E 这 6 个突变体被预测为通过蛋白质稳定性分析在结构和功能上具有破坏性。此外，这些变体位于进化保守区域，要么被埋藏，导致结构损伤，要么暴露，导致蛋白质功能发生变化。这些变体进一步进行了分子对接研究。当通过实验分析验证时，SNP M108V(rs149798710)、N86H(rs151039853)和 V79E(rs17854505)与 2 型糖尿病（T2DM）相关。rs149798710(A>G)的次要等位基因频率在对照组中为 0.23，在二甲双胍应答者中为 0.29，在二甲双胍无应答者中为 0.37；rs151039853(A>C)在对照组中为 0.21，在二甲双胍应答者中为 0.28，在二甲双胍无应答者中为 0.36；rs17854505(T>A)在对照组中为 0.20，在二甲双胍应答者中为 0.25，在二甲双胍无应答者中为 0.37。因此，本研究得出结论，SLC29A4 M108V(rs149798710)、N86H(rs151039853)和 V79E(rs17854505)多态性与 T2DM 的发病风险增加以及巴基斯坦 T2DM 患者二甲双胍治疗反应失败的风险增加有关。由 Ramaswamy H. Sarma 传达。
