Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene
Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene
复制标题
抗病毒 2′,5′-寡腺苷酸合成酶（2′5′AS）酶活性的变化受 OAS1 基因中剪接接受位点单核苷酸多态性的控制
DOI：
10.1086/429391
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发表时间：
2005-04-01
影响因子：
9.8
通讯作者：
Pociot, F
中科院分区：
文献类型：
--
作者：
Bonnevie-Nielsen, V;Field, LL;Pociot, F
人类遗传差异可能介导对病毒感染和病毒引发的疾病的易感性。编码抗病毒酶2 '，5'-寡腺苷酸合成酶（2 '5'AS）的OAS基因是对病毒的先天免疫应答的关键组分。这种酶在2 '-特异性核苷酸转移反应中使用三磷酸腺苷合成2'，5 '-寡腺苷酸，其激活潜伏的核糖核酸酶，导致病毒RNA的降解和病毒复制的抑制。我们在其他地方表明，2 '5'AS的组成型（基础）活性与病毒刺激活性相关。在本研究中，我们问是否组成活动是遗传决定的，如果是这样，由哪些变体。对83个包含双亲和两个孩子的家庭的分析表明，父母-孩子对（P < .0001）和兄弟姐妹对（P = .0044）的基础活动之间存在显著相关性，但配偶对之间没有相关性，这表明基础活动具有很强的遗传控制。接下来，我们分析了基础活性与OAS基因簇中的15个标志物之间的关联。在多个标记中检测到显著关联，最强的是OAS 1基因外显子7剪接受体位点（AG或AA）的A/G单核苷酸多态性。在这种不寻常的多态性中，等位基因G在高酶活性人群中的基因频率高于低酶活性人群（0.44 vs. 0.20; P = 3 × 10 - 11）。在GG、GA和AA基因型中，酶活性以剂量-P依赖性方式变化（通过方差分析检验; P = 1 x 10（-14））。等位基因G产生先前描述的p46酶同种型，而等位基因A消融剪接位点并产生双重功能的抗病毒/促凋亡p48同种型和新的p52同种型。这种遗传多态性使OAS 1成为影响宿主对病毒感染易感性的人类基因的极好候选者。
It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2', 5'-oligoadenylate synthetase (2'5'AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2', 5'-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2'5'AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P < .0001) and sibling pairs (P = .0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P = 3 x 10(-11)). Enzyme activity varied in a dose-P dependent manner across the GG, GA, and AA genotypes ( tested by analysis of variance; P = 1 x 10(-14)). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.