A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders
A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders
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DOI：
10.1167/iovs.17-23027
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发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Reynier, Pascal
中科院分区：
文献类型：
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作者：
Bocca, Cinzia;Nzoughet, Judith Kouassi;Reynier, Pascal
目的。显性视神经萎缩（DOA； MIM[孟德尔遗传]165500）导致视网膜神经节细胞变性，主要是由视神经萎缩1 （OPA1）基因突变引起的，该基因编码参与线粒体膜加工的动力蛋白鸟苷三磷酸（GTP）酶。这项工作旨在确定来自OPA1致病变异携带者的血浆是否显示出特定的代谢特征。我们应用了基于超高压液相色谱耦合高分辨率质谱（UHPLC-HRMS）的非靶向临床代谢组学管道，允许探索血浆中的500种极性代谢物。我们比较了25名不同OPA1致病变异和表型的患者与20名健康对照者的血浆代谢谱。采用单变量和多变量（主成分分析[PCA]、正交偏最小二乘判别分析[OPLS-DA]）方法和机器学习方法Biosigner算法进行统计分析。基于改变浓度的复杂代谢物面板，获得了表征OPA1个体的可靠且相关的预测模型。嘌呤代谢的损害，包括黄嘌呤、次黄嘌呤和肌苷浓度的显著差异，是该特征的前景。此外，尿酸盐、胆碱、磷胆碱、甘油、1-油酰丙三醇、丙三醇肉豆蔻酸盐、天冬氨酸、谷氨酸和胱氨酸浓度的差异也表征了该特征。这是在携带OPA1致病变异的患者血浆中报道的第一个代谢特征，突出了嘌呤代谢在DOA病理生理中的意外参与。
PURPOSE. Dominant optic atrophy (DOA; MIM [Mendelian Inheritance in Man] 165500), resulting in retinal ganglion cell degeneration, is mainly caused by mutations in the optic atrophy 1 (OPA1) gene, which encodes a dynamin guanosine triphosphate (GTP)ase involved in mitochondrial membrane processing. This work aimed at determining whether plasma from OPA1 pathogenic variant carriers displays a specific metabolic signature.METHODS. We applied a nontargeted clinical metabolomics pipeline based on ultra-high-pressure liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) allowing the exploration of 500 polar metabolites in plasma. We compared the plasma metabolic profiles of 25 patients with various OPA1 pathogenic variants and phenotypes to those of 20 healthy controls. Statistical analyses were performed using univariate and multivariate (principal component analysis [PCA], orthogonal partial least-squares discriminant analysis [OPLS-DA]) methods and a machine learning approach, the Biosigner algorithm.RESULTS. A robust and relevant predictive model characterizing OPA1 individuals was obtained, based on a complex panel of metabolites with altered concentrations. An impairment of the purine metabolism, including significant differences in xanthine, hypoxanthine, and inosine concentrations, was at the foreground of this signature. In addition, the signature was characterized by differences in urocanate, choline, phosphocholine, glycerate, 1-oleoyl-rac-glycerol, rac-glycerol-l-myristate, aspartate, glutamate, and cystine concentrations.CONCLUSIONS. This first metabolic signature reported in the plasma of patient carrying OPA1 pathogenic variants highlights the unexpected involvement of purine metabolism in the pathophysiology of DOA.