Richardson Matthew R, Segu Zaneer M, Price Marianne O, Lai Xianyin, Witzmann Frank A, Mechref Yehia, Yoder Mervin C, Price Francis W
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46260, USA.
Mol Vis. 2010 Nov 11;16:2376-83.
Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by corneal endothelial decompensation leading to corneal edema, clouding, and vision impairment. Despite improved understanding over the last century since its first description, the exact mechanism(s) behind the pathogenesis of FECD remain unknown, and surgical correction is the only effective treatment available. Previous studies have suggested a role for changes in aqueous humor (AH) composition in FECD pathogenesis, so to explore this possibility, we probed the AH proteome for alterations correlating with end-stage corneal disease. Following albumin depletion we performed label-free quantitative tandem mass spectrometry on proteins isolated from patients with and without FECD who were scheduled to undergo routine cataract extraction. We identified 64 proteins, most of which were identified in previous AH proteomic studies of patients with cataracts, in the albumin-depleted fraction. The levels of five of these were significantly lower (afamin, complement C3, histidine-rich glycoprotein, immunoglobulin heavy [IgH], and protein family with sequence similarity 3, member C [FAM3C]), while the levels of one (suprabasin) was significantly higher in patients with FECD compared to controls (p≤0.01). We also identified 34 proteins in the albumin-bound fraction, four of which were significantly elevated in patients with FECD including a hemoglobin fragment, immunoglobulin kappa (IgK), immunoglobulin lambda (IgL), and uncharacterized protein albumin (ALB), (p≤0.01). Although it has been reported that females have a greater extent of disease than males, we were unable to detect any significant differences in protein levels due to gender. Because FECD is a progressive disorder, regression analyses were performed to determine any significant correlations with age, and of interest retinol-binding protein 3 was significantly correlated with age in patients with FECD (p≤0.01), whereas no proteins in the control group correlated with age. This is the first report indicating alterations in the AH proteome with FECD, and taken together this study suggests several novel hypotheses regarding AH proteins role in FECD pathogenesis.
富克斯内皮性角膜营养不良（FECD）是一种进行性疾病，其特征是角膜内皮失代偿，导致角膜水肿、混浊和视力损害。尽管自首次描述以来的上个世纪人们对其认识有所提高，但FECD发病机制背后的确切机制仍然未知，手术矫正仍是唯一有效的治疗方法。先前的研究表明房水（AH）成分的变化在FECD发病机制中起作用，因此为了探索这种可能性，我们检测了AH蛋白质组中与终末期角膜疾病相关的改变。在去除白蛋白后，我们对计划接受常规白内障摘除术的有和没有FECD的患者分离出的蛋白质进行了无标记定量串联质谱分析。我们鉴定出64种蛋白质，其中大多数在先前对白内障患者的AH蛋白质组学研究中在去除白蛋白的组分中被鉴定出来。其中五种蛋白质的水平显著降低（afamin、补体C3、富含组氨酸的糖蛋白、免疫球蛋白重链[IgH]和序列相似性3成员C蛋白质家族[FAM3C]），而与对照组相比，FECD患者中一种蛋白质（上层基底蛋白）的水平显著升高（p≤0.01）。我们还在白蛋白结合组分中鉴定出34种蛋白质，其中四种在FECD患者中显著升高，包括血红蛋白片段、免疫球蛋白κ（IgK）、免疫球蛋白λ（IgL）和未鉴定的蛋白质白蛋白（ALB）（p≤0.01）。尽管有报道称女性的病情比男性更严重，但我们未能检测到由于性别导致的蛋白质水平有任何显著差异。由于FECD是一种进行性疾病，我们进行了回归分析以确定与年龄的任何显著相关性，有趣的是，视黄醇结合蛋白3在FECD患者中与年龄显著相关（p≤0.01），而对照组中没有蛋白质与年龄相关。这是第一份表明FECD患者AH蛋白质组发生改变的报告，综合来看，这项研究提出了几个关于AH蛋白质在FECD发病机制中作用的新假设。
