In Silico Screening and Molecular Dynamic Study of Nonsynonymous Single Nucleotide Polymorphisms Associated with Kidney Stones in the SLC26A6 Gene
In Silico Screening and Molecular Dynamic Study of Nonsynonymous Single Nucleotide Polymorphisms Associated with Kidney Stones in the SLC26A6 Gene
复制标题
SLC26A6 基因中与肾结石相关的非同义单核苷酸多态性的计算机筛选和分子动力学研究。
DOI：
10.1016/j.juro.2016.01.093
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发表时间：
2016-07-01
影响因子：
6.6
通讯作者：
Gao, Bing
中科院分区：
文献类型：
--
作者：
Lu, Xiuli;Sun, Deliang;Gao, Bing
目的：SLC26A6是一种多功能阴离子转运蛋白，在草酸盐阴离子的转运中具有重要的生理作用。识别SLC26A6的遗传变异将促进我们对草酸钙结石形成过程中草酸盐运输的理解。材料和方法：使用4种计算机工具（SIFT (Sorting Intolerant From tolerance)）、PROVEAN （Protein Variation Effect Analyzer）、PhD-SNP（人类有害单核苷酸多态性预测因子）和MutPred对SLC26A6中报道的所有非同义单核苷酸多态性进行了研究。采用等位基因特异性聚合酶链反应对候选疾病相关nsSNP进行基因分型，共纳入426名受试者，其中包括225名肾结石患者和201名健康对照。此外，利用同源性建模和分子动力学模拟方法评估了突变引起的结构后果。结果：通过硅筛选，nsSNP rs184187143被鉴定为SLC26A6基因中更可能的疾病相关变异。在nsSNP中，C等位基因携带者患肾结石的风险是G等位基因携带者的6.1倍（OR 6.1, 95% CI 1.36-27.38, p = 0.007）。我们发现，从精氨酸到甘氨酸的突变导致SLC26A6的STAS结构域失去2个氢键，结构不稳定。结论：我们的研究结果表明SLC26A6基因变异G539R与肾结石风险相关，为进一步了解肾结石形成过程中草酸盐的转运提供了明确的线索。
Purpose: SLC26A6 is a multifunctional anion transporter with a critical physiological role in the transport of oxalate anions. Recognizing a genetic variant of SLC26A6 would advance our understanding of oxalate transport in the formation of calcium oxalate stones.Materials and Methods: All nsSNPs (nonsynonymous single nucleotide polymorphisms) reported in human SLC26A6 were investigated using 4 in silico tools, including SIFT (Sorting Intolerant From Tolerant), PROVEAN (Protein Variation Effect Analyzer), PhD-SNP (Predictor of human Deleterious Single Nucleotide Polymorphisms) and MutPred. A total of 426 subjects, including 225 with kidney stones and 201 healthy controls, were included in study to genotype the candidate disease associated nsSNP using allele specific polymerase chain reaction. Furthermore, the structural consequences due to the mutation were assessed using homology modeling and molecular dynamics simulation methods.Results: The nsSNP rs184187143 was identified as a more probable disease associated variant in the SLC26A6 gene by in silico screening. The C allele carrier showed a 6.1-fold increased kidney stone risk compared with G allele carriers in the nsSNP (OR 6.1, 95% CI 1.36-27.38, p = 0.007). We found that the mutation from arginine to glycine leads to the loss of 2 hydrogen bonds and to an unstable structure in the STAS domain of SLC26A6.Conclusions: Our results indicate that the variant G539R in the SLC26A6 gene is associated with kidney stone risk, providing a clear clue to further achieve insight into oxalate transport in kidney stone formation.