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首页> 外文期刊>Genetic testing and molecular biomarkers >IMPDH2 Genetic Polymorphism:A Promoter Single-Nucleotide Polymorphism Disrupts a Cyclic Adenosine Monophosphate Responsive Element
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IMPDH2 Genetic Polymorphism:A Promoter Single-Nucleotide Polymorphism Disrupts a Cyclic Adenosine Monophosphate Responsive Element

机译：IMPDH2遗传多态性:启动子单核苷酸多态性破坏循环腺苷酸反应元素

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摘要

Inosine S'-monophosphate dehydrogenase (IMPDH), which catalyzes a key step in the de novo biosynthesis of guanine nucleotide, is mediated by two highly conserved isoforms, IMPDH1 and IMPDH2. In this study, IMPDH2 genetic polymorphism was investigated in 96 individuals of Caucasian origin. Four single-nucleotide polymorphisms were identified, comprising one previously described single base-pair substitution in the close vicinity of the consensus donor splice site of intron 7 (IVS7+10T>C), and three novel polymorphisms, one silent substitution in exon 9 (c.915C>G), one single base-pair insertion (g.6971_6972insT) within the 3'-untranslated region of the gene, and one substitution located in the promoter region (c.-95T>G) in a transcription factor binding site CRE(A) ( cyclic adenosine monophosphate [CAMP] response element). Considering the nature and location of this latter polymorphism, its functional relevance was examined by transfecting HEK293 and Jurkat cell lines with constructs of the related region of IMPDH2/luciferase reporter gene. The c.-95T>G mutation leads to a significant decrease of luciferase activity (HEK293: 55% decrease, p < 0.05; Jurkat: 65% decrease, p < 0.05) compared with the wild-type promoter sequence and, therefore, is likely to determine interindividual differences in IMPDH2 transcriptional regulation. These results might contribute to a better understanding of the variability in clinical outcome and dose adjustments of certain immunosuppressors that are metabolized through the IMPDH pathway or that are IMPDH inhibitors.
机译：肌苷年代一磷酸脱氢酶(IMPDH),催化在新创一个关键步骤鸟嘌呤核苷酸的生物合成,是介导由两个高度保守的亚型,IMPDH1和IMPDH2。多态性在96年被调查的人白人血统。多态性,组成一个先前描述的单一碱基对替换接近附近的共识的剪接供体基因内区7(IVS7 + 10 t > C)和三个小说多态性沉默替代外显子9 (c.915C > G),一个单碱基对插入(g.6971_6972insT)在3 '非翻译区基因,和一个替换位于启动子区域(c - 95 t > G)转录因子结合位点CRE (A)(环腺一磷酸(营)响应元素)。考虑的性质和位置后一种多态性,其功能相关性检查使转染HEK293细胞和Jurkat线条与结构相关的区域IMPDH2 /荧光素酶报告基因。突变导致的显著下降荧光素酶活性(HEK293:减少55%,p <0.05;与野生型启动子序列,因此,很可能会决定个人间IMPDH2转录调节的差异。这些结果可能会导致一个更好的了解临床的可变性结果,特定的剂量调整通过代谢免疫抑制IMPDH通路或IMPDH抑制剂。

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