Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes
Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes
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DOI：
10.1016/j.bbabio.2014.01.021
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发表时间：
2014-07-01
影响因子：
4.3
通讯作者：
Kaguni, Laurie S.
中科院分区：
文献类型：
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作者：
Farnum, Gregory A.;Nurminen, Anssi;Kaguni, Laurie S.
我们通过完善之前描述的将人类 POLG 基因中的致病性突变映射到线粒体复制酶 Polls 催化核心中的功能簇的方案，建立了全谱 POLG 综合征的基因型-表型相关性 (1)。我们将 136 个突变分配给 5 个簇，并识别可用于界定每个簇边界的一级序列片段。我们报告说，具有来自不同簇的两个突变的复合杂合子表现出更严重的、早发的 POLG 综合征，而来自同一簇的两个突变不太常见，并且通常与不太严重的、晚发的 POLG 综合征相关。我们还表明，特定的集群组合比其他集群组合更严重，并且更有可能在较早的年龄表现出来。我们的聚类方法提供了一个强大的工具来预测 POLG（线粒体疾病最常见的核基因）的新变异和突变的致病潜力和疾病表型。我们建议这种预测工具对于线粒体疾病的常规诊断很有用。本文是题为“第 18 届欧洲生物能会议”的特刊的一部分。 (C) 2014 Elsevier B.V. 保留所有权利。
We establish the genotype-phenotype correlations for the complete spectrum of POLG syndromes by refining our previously described protocol for mapping pathogenic mutations in the human POLG gene to functional clusters in the catalytic core of the mitochondrial replicase, Polls (1). We assigned 136 mutations to five clusters and identify segments of primary sequence that can be used to delimit the boundaries of each cluster. We report that compound heterozygotes with two mutations from different clusters manifested more severe, earlier-onset POLG syndromes, whereas two mutations from the same cluster are less common and generally are associated with less severe, later onset POLG syndromes. We also show that specific cluster combinations are more severe than others and have a higher likelihood to manifest at an earlier age. Our clustering method provides a powerful tool to predict the pathogenic potential and predicted disease phenotype of novel variants and mutations in POLG, the most common nuclear gene underlying mitochondrial disorders. We propose that such a prediction tool would be useful for routine diagnostics for mitochondrial disorders. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. (C) 2014 Elsevier B.V. All rights reserved.