Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations.
Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations.
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CYP21A2稳定性变体的基于结构的活性预测：可用基因变异的调查。
DOI：
10.1038/srep39082
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发表时间：
2016-12-14
影响因子：
4.6
通讯作者：
Dain L
中科院分区：
文献类型：
--
作者：
Bruque CD;Delea M;Fernández CS;Orza JV;Taboas M;Buzzalino N;Espeche LD;Solari A;Luccerini V;Alba L;Nadra AD;Dain L
由于21-羟化酶缺乏引起的先天性肾上腺皮质增生占CAH病例的90-95%。在这项工作中，我们进行了广泛的调查突变和单核苷酸多态性修饰的CYP 21 A2基因的编码序列。使用生物信息学工具和两个合理的CYP 21 A2结构作为模板，我们最初根据其推定的功能影响对所有已知突变体（n = 343）进行分类，这些功能影响要么在文献中报道，要么从结构模型中推断。然后，我们对被认为专门影响蛋白质稳定性的突变子集进行了详细分析。对于这些突变体，计算预测的稳定性并与变体的预期活性相关联。当我们的预测与可用的体外残留活性和/或患者的表型进行比较时，获得了很高的一致性。评估了所有报告的突变和缺乏功能测定的SNP（n = 108）的预测稳定性和衍生活性。正如预期的那样，大多数SNPs（52/76）没有显示出生物学意义。此外，这种方法被应用于评估当两个突变发生在顺式时可能出现的推定的协同作用。此外，我们提出了一个假定的致病作用的五个新的突变，p.L107Q，p.L122R，p.R132H，p.P335L和p.H466fs，发现在21-羟化酶缺乏患者的队列。
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90–95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant’s expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient’s phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort.
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影响因子：
3.2
作者：
Baradaran-Heravi, Alireza;Vakili, Rahim;Abbaszadegan, Mohammad Reza
通讯作者：
Abbaszadegan, Mohammad Reza
影响因子：
5.8
作者：
Deneux, C;Tardy, V;Kuttenn, F
通讯作者：
Kuttenn, F
影响因子：
2.9
作者：
Bronstad, Ingeborg;Breivik, Lars;Husebye, Eystein S.
通讯作者：
Husebye, Eystein S.
DOI：
10.1093/bioinformatics/btq662
发表时间：
2011-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Benkert P;Biasini M;Schwede T
通讯作者：
Schwede T
影响因子：
5.3
作者：
Bojunga, J;Welsch, C;Zeuzem, S
通讯作者：
Zeuzem, S