Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States.
Hybrigenics Services, Paris, France.
Invest Ophthalmol Vis Sci. 2018 Apr 1;59(5):1751-1759. doi: 10.1167/iovs.17-23277.
We investigate the function of the V83I polymorphism (m.6150G>A, rs879053914) in the mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) gene and its role in African American (AA) primary open-angle glaucoma (POAG).
This study used Sanger sequencing (1339 cases, 850 controls), phenotypic characterization of Primary Open-Angle African American Glaucoma Genetics study (POAAGG) cases, a masked chart review of CO1 missense cases (V83I plus M117T, n = 29) versus wild type cases (n = 29), a yeast 2-hybrid (Y2H) cDNA library screen, and quantification of protein-protein interactions by Y2H and ELISA.
The association of V83I with POAG in AA was highly significant for men (odds ratio [OR] 6.5; 95% confidence interval [CI] 2.0-21.3, P = 0.0001), but not for women (OR 1.1; 95% CI, 0.62-2.00, P = 0.78). POAG cases having CO1 double missense mutation (V83I + M117T, L1c2 haplogroup) had a higher cup-to-disc ratio (0.77 vs. 0.71, P = 0.04) and significantly worse visual function (average pattern standard deviation, 6.5 vs. 4.3, P = 0.009; average mean deviation -10.4 vs. -4.5, P = 0.006) when compared to matched wild type cases (L1b haplogroup). Interaction of the V83I region of CO1 with amyloid beta peptide (Aβ) was confirmed by ELISA assay, and this interaction was abrogated by V83I. A Y2H screen of an adult human brain cDNA library with the V83 region of CO1 as bait retrieved the UBQLN1 gene.
The V83I polymorphism was associated strongly with POAG in AA men and disrupts Aβ-binding to CO1. This region also interacts with a neuroprotective protein, UBQLN1.
我们研究了线粒体细胞色素 c 氧化酶亚基 1（MT-CO1）基因中 V83I 多态性（m.6150G>A，rs879053914）的功能及其在非裔美国人（AA）原发性开角型青光眼（POAG）中的作用。
本研究采用 Sanger 测序（1339 例病例，850 例对照）、原发性开角型非洲裔美国人青光眼遗传学研究（POAAGG）病例的表型特征分析、CO1 错义病例（V83I 加 M117T，n=29）与野生型病例（n=29）的盲法图表回顾、酵母 2-杂交（Y2H）cDNA 文库筛选以及 Y2H 和 ELISA 定量蛋白-蛋白相互作用。
V83I 与 AA 中 POAG 的关联在男性中非常显著（优势比[OR]6.5；95%置信区间[CI]2.0-21.3，P=0.0001），但在女性中不显著（OR 1.1；95%CI，0.62-2.00，P=0.78）。具有 CO1 双重错义突变（V83I+M117T，L1c2 单倍群）的 POAG 病例杯盘比更高（0.77 比 0.71，P=0.04），视觉功能明显更差（平均模式标准差，6.5 比 4.3，P=0.009；平均平均偏差-10.4 比-4.5，P=0.006）与匹配的野生型病例（L1b 单倍群）相比。通过 ELISA 测定证实了 CO1 的 V83I 区域与淀粉样β肽（Aβ）的相互作用，并且这种相互作用被 V83I 破坏。用 CO1 的 V83 区域作为诱饵进行成人脑 cDNA 文库的 Y2H 筛选，检索到 UBQLN1 基因。
V83I 多态性与 AA 男性中的 POAG 强烈相关，并破坏 Aβ 与 CO1 的结合。该区域还与神经保护蛋白 UBQLN1 相互作用。
