Predicting the pathogenicity of RPE65 mutations.
Predicting the pathogenicity of RPE65 mutations.
复制标题
DOI：
10.1002/humu.21033
复制
发表时间：
2009-08
期刊：
影响因子：
3.9
通讯作者：
Stone, Edwin M.
中科院分区：
文献类型：
--
作者：
Philpa, A. R.;Jin, M.;Li, S.;Schindler, E. I.;Iannaccone, A.;Lam, B. L.;Weleber, R. G.;Fishman, G. A.;Jacobson, S. G.;Mullins, R. F.;Travis, Gabriel H.;Stone, Edwin M.
为了帮助区分致病突变和非致病性多态性，我们开发了一种客观的算法来计算“致病概率估计”（EPP），该算法基于特定变异的流行程度、其在家族中的分离程度以及其对蛋白质结构的预测影响。采用EPP算法对Leber先天性黑朦（LCA）患者RPE65基因的11个错义变异进行了评估。EPP算法的准确性通过RPE65异构酶活性的细胞培养实验来评估。这些变异被设计到含有人RPE65 cDNA的质粒中，并在培养的细胞中测定每个变异的类视黄醇异构酶活性。EPP算法预测了8个替代突变是致病变异。这些RPE65变异的异构酶催化活性均低于野生型的6%。相比之下，EPP算法预测其他三个替换为非致病，其异构酶活性分别为野生型的68%，127%和110%。我们观察到RPE65基因错义变异的预测致病性与在功能分析中测量的类视黄醇异构酶活性之间完全一致。这些结果表明，EPP算法可能有助于评估其他疾病基因错义变异的致病性，而这些疾病基因的功能分析是不可用的。
To assist in distinguishing disease-causing mutations from non-pathogenic polymorphisms, we developed an objective algorithm to calculate an “estimate of pathogenic probability” (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127% and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.
登录
查看更多内容
影响因子：
4.8
作者：
Mata, NL;Moghrabi, WN;Travis, GH
通讯作者：
Travis, GH
DOI：
10.1073/pnas.0503460102
发表时间：
2005-08-30
影响因子：
11.1
作者：
Moiseyev, G;Chen, Y;Ma, JX
通讯作者：
Ma, JX
影响因子：
4.8
作者：
Takahashi, Yusuke;Chen, Ying;Ma, Jian-Xing
通讯作者：
Ma, Jian-Xing
影响因子：
2.9
作者：
Bereta, Grzegorz;Kiser, Philip D.;Golczak, Marcin;Sun, Wenyu;Heon, Elise;Saperstein, David A.;Palczewski, Krzysztof
通讯作者：
Palczewski, Krzysztof
影响因子：
4.2
作者：
Stone, Edwin M.
通讯作者：
Stone, Edwin M.