Three-dimensional structural location and molecular functional effects of missense SNPs in the T cell receptor Vbeta domain.
Three-dimensional structural location and molecular functional effects of missense SNPs in the T cell receptor Vbeta domain.
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T细胞受体Vbeta结构域中错义SNP的三维结构位置和分子功能效应。
DOI：
10.1002/prot.10522
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Moult,John
中科院分区：
文献类型：
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作者：
Wang,Zhen;Moult,John
人类单核苷酸多态性（SNPs）影响疾病易感性的机制尚未得到很好的理解。在先前的研究中，我们开发了一种基于结构的模型，该模型可用于鉴定哪些错义SNP是中性的，哪些对蛋白质功能有害，因此可能参与疾病（Wang和Moult，MüttzMutat 2001;263-270）。该模型现已应用于46个功能性T细胞受体Vβ基因中的一组54个错义cSNP。这些错义cSNP中的大多数被发现是中性的，但10个被鉴定为可能对蛋白质功能有害。只有一个以前与疾病有关。我们认为其他可能与疾病有关，但T细胞反应中的冗余阻止了任何简单的单基因效应。因此，这些SNP是复杂的多基因疾病性状的最可能贡献者。已经注意到，在这些基因中存在令人惊讶的高比例（74%）的非同义SNP。与预期相反，分析表明这些与异常高比例的有害SNP无关，也不会显著促进更大范围的抗原识别或减少超抗原结合库。Proteins 2003.© 2003 Wiley利斯公司
The mechanisms by which human single nucleotide polymorphisms (SNPs) influence susceptibility to disease are not yet well understood. In a previous study, we developed a structure‐based model that may be used to identify which missense SNPs are neutral and which are deleterious to protein function and so potentially involved in disease (Wang and Moult, Hum Mutat 2001;263–270). The model has now been applied to a set of 54 missense cSNPs in the 46 functional T‐cell receptor Vβ‐genes. Most of these missense cSNPs are found to be neutral, but 10 are identified as likely deleterious to protein function. Only one was previously associated with disease. We suggest that the others may be disease related but that redundancy in the T‐cell response prevents any simple, monogenic effect. Therefore, these SNPs are the most likely contributors to complex, polygenic disease traits. It has been noted that there is a surprisingly high (74%) fraction of nonsynonymous SNPs in these genes. Contrary to expectation, the analysis shows that these are not associated with an unusually high fraction of deleterious SNPs, nor do they significantly contribute to a larger range of antigen recognition or a reduced superantigen‐binding repertoire. Proteins 2003. © 2003 Wiley‐Liss, Inc.