Silent SNPs: impact on gene function and phenotype
Silent SNPs: impact on gene function and phenotype
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DOI：
10.2217/14622416.8.8.1075
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发表时间：
2007-08-01
期刊：
影响因子：
2.1
通讯作者：
Komar, Anton A.
中科院分区：
文献类型：
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作者：
Komar, Anton A.
在编码P-糖蛋白的MDR 1基因中携带沉默SNP的个体有时会显示出P-糖蛋白药代动力学的改变。目前还没有合理的解释为什么沉默的SNP可能有这样的影响，特别是当没有变化的P-糖蛋白mRNA和蛋白质的表达水平已被观察到。本研究的目的是进行仔细的离体（在细胞内）分析的三个多态性（C1236 T，G2677 T C3435 T）对P-糖蛋白的表达和活性的影响。因此，已经显示MDR 1中的沉默多态性（特别是C3435 T）可以改变P-糖蛋白构象和蛋白质活性/底物特异性。这项研究非常重要，因为它首次证明了天然存在的沉默SNP可以导致合成具有相同氨基酸序列但不同结构和功能特性的蛋白质产物。因此，在确定各种疾病发展的可能性时，不应再忽视沉默SNP，而应在个性化药物治疗和开发计划中加以考虑。
Individuals carrying silent SNPs in the MDR1 gene encoding P-glycoprotein sometimes reveal altered P-glycoprotein pharmacokinetics. There is no rational explanation for why silent SNPs might have such effects, especially when no change in P-glycoprotein mRNA and protein expression levels has been observed. The purpose of this study was to perform careful ex vivo (in cells) analysis of the effects of the three polymorphisms (C1236T, G2677T C3435T) on P-glycoprotein expression and activity. As a result, it has been shown that silent polymorphisms (in particular, C3435T) in MDR1 can alter P-glycoprotein conformation and protein activity/substrate specificity. This study is of immense importance as it demonstrates for the first time that naturally occurring silent SNPs can lead to the synthesis of protein product with the same amino acid sequence but different structural and functional properties. Thus, silent SNPs should no longer be neglected in determining the likelihood of development of various diseases, and should be taken into account in personalized drug treatment and development programs.