Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor
Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor
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DOI：
10.1093/hmg/ddg055
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发表时间：
2003-02-01
影响因子：
3.5
通讯作者：
Gejman, PV
中科院分区：
文献类型：
--
作者：
Duan, JB;Wainwright, MS;Gejman, PV
虽然核苷酸序列的变化影响蛋白质的组成和结构是众所周知的，但核苷酸取代导致的功能变化并不总是能从DNA序列的简单分析中推断出来。由于人类DRD2基因中存在强烈的同义密码子使用偏差，表明同义位置的选择，第三个密码子位置的G+C含量相对独立于等线G+C频率，因此我们选择研究人类DRD2基因中已知的六种自然发生的同义变化（C132T, G423A, T765C, C939T， C957T和G1101A）的功能影响。我们在这里报道了人类DRD2中的一些同义突变具有功能效应，并提出了一种新的遗传机制。957T并非“沉默”，而是改变了预测的mRNA折叠，导致mRNA稳定性和翻译降低，并显著改变了多巴胺诱导的DRD2表达上调。1101 A在复合克隆957T/ 1101 A中没有表现出单独的效应，但抵消了957T的上述效应，这表明同义突变的组合可能具有与单个分离突变截然不同的功能后果。C957T在欧美人群中与-141C Ins/Del和TaqI ‘ a ’变异存在连锁不平衡，据报道，这两种变异分别与精神分裂症和酒精中毒有关。这些结果对分子群体遗传学和复杂遗传疾病基因作图研究中关于同义变异的一些假设提出了质疑，并表明同义变异可能具有潜在的病理生理和药物遗传学重要性。
Although changes in nucleotilde sequence affecting the composition and the structure of proteins are well known, functional changes resulting from nucleotide substitutions cannot always be inferred from simple analysis of DNA sequence. Because a strong synonymous codon usage bias in the human DRD2 gene, suggesting selection on synonymous positions, was revealed by the relative independence of the G+C content of the third codon positions from the isochoric G+C frequencies, we chose to investigate functional effects of the six known naturally occurring synonymous changes (C132T, G423A, T765C, C939T, C957T, and G1101A) in the human DRD2. We report here that some synonymous mutations in the human DRD2 have functional effects and suggest a novel genetic mechanism. 957T, rather than being 'silent', altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced up-regulation of DRD2 expression. 1101 A did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1 101 A, demonstrating that combinations of synonymous mutations can have functional consequences drastically different from those of each isolated mutation. C957T was found to be in linkage disequilibrium in a European-American population with the -141C Ins/Del and TaqI 'A' variants, which have been reported to be associated with schizophrenia and alcoholism, respectively. These results call into question some assumptions made about synonymous variation in molecular population genetics and gene-mapping studies of diseases with complex inheritance, and indicate that synonymous variation can have effects of potential pathophysiological and pharmacogenetic importance.