Enhanced accumulation of A2E in individuals homozygous or heterozygous for mutations in BEST1 (VMD2)
Enhanced accumulation of A2E in individuals homozygous or heterozygous for mutations in BEST1 (VMD2)
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DOI：
10.1016/j.exer.2007.02.018
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发表时间：
2007-07-01
影响因子：
3.4
通讯作者：
Marmorstein, A. D.
中科院分区：
文献类型：
--
作者：
Bakall, B.;Radu, R. A.;Marmorstein, A. D.
最佳卵黄状黄斑营养不良（BMD）是一种常染色体显性遗传性黄斑变性疾病，由基因BEST 1（以前称为VMD 2）突变引起。先前的报告表明，BMD的组织病理学特征是视网膜色素上皮（RPE）中脂褐素的积累。然而，这种积累尚未被量化，BMD中脂褐素的化学组成也未被检测。在这项研究中，我们的特点是供体眼的组织病理学从一个罕见的个体纯合子突变（W93C）BEST 1。我们发现这个人的疾病并不比杂合子更严重。然后，我们使用该组织通过在蔗糖梯度上富集来自RPE细胞的细胞内颗粒并计数每个密度级分中的颗粒来定量脂褐素积累。将来自纯合供体眼以及来自突变T6R杂合个体的供体眼的颗粒与年龄匹配的对照眼进行比较。有趣的是，代表经典脂褐质颗粒的最低密度部分在BNID供体眼中不存在或显著减少，并且与脂褐质相关的自荧光已经转移到更致密的部分。然而，在BMD样品中也注意到较高密度部分中颗粒的大量富集。通过电子显微镜检查纯合子供体眼中的颗粒，发现了复杂的异常多小叶结构。通过HPLC对颗粒的分析表明，与年龄匹配的对照眼相比，BMD眼的A2E总体增加了1.6倍和4倍，BNID供体眼的A2E向更致密的颗粒转移。尽管A2E和总细胞内颗粒增加，但纯合子供体眼中的RPE相对保存良好。基于这些数据，我们得出结论，临床和组织病理学后果的纯合子供体没有任何更严重的比以前已报告的个人谁是建立或假定的杂合子。我们发现A2E是BMD中积累的脂褐素的一个组成部分，并且它比对照眼更丰富，这表明BMD的病因与Stargardt病和Stargardt样黄斑营养不良相似。最后，我们在颗粒中观察到的变化表明，与BMD相关的组织病理学和最终视力丧失可能是由于RPE完全降解吞噬的光感受器外节的能力缺陷。(c)2007爱思唯尔有限公司保留所有权利。
Best vitelliform macular dystrophy (BMD) is an autosomal dominant inherited macular degenerative disease caused by mutations in the gene BEST1 (formerly VMD2). Prior reports indicate that BMD is characterized histopathologically by accumulation of lipofuscin in the retinal pigment epithelium (RPE). However, this accumulation has not been quantified and the chemical composition of lipofuscin in BMD has not been examined. In this study we characterize the histopathology of a donor eye from a rare individual homozygous for a mutation (W93C) in BEST1. We find that this individual's disease was not any more severe than has been described for heterozygotes. We then used this tissue to quantify lipofuscin accumulation by enriching intracellular granules from RPE cells on sucrose gradients and counting the granules in each density fraction. Granules from the homozygous donor eye as well as a donor eye from an individual heterozygous for the mutation T6R were compared with age-matched control eyes. Interestingly, the least dense fraction, representing classical lipofuscin granules was either not present or significantly diminished in the BNID donor eyes and the autoflourescence associated with lipofuscin had shifted to denser fractions. However, a substantial enrichment for granules in fractions of higher density was also noted in the BMD samples. Inspection of granules from the homozygous donor eye by electron microscopy revealed a complex abnormal multilobular structure. Analysis of granules by HPLC indicated a similar to 1.6- and similar to fourfold overall increase in A2E in the BMD eyes versus age-matched control eyes, with a shift of A2E to more dense granules in the BNID donor eyes. Despite the increase in A2E and total intracellular granules, the RPE in the homozygous donor eyes was relatively well preserved. Based on these data we conclude that the clinical and histopathologic consequences to the homozygous donor were not any more severe than has been reported previously for individuals who are established or presumptive heterozygotes. We find that A2E is a component of the lipofuscin accumulated in BMD and that it is more abundant than in control eyes suggesting that the etiology of BMD is similar to Stargardt's disease and Stargardt-like macular dystrophy. Finally, the changes we observe in the granules suggest that the histopathology and eventual vision loss associated with BMD may be due to defects in the ability of the RPE to fully degrade phagocytosed photoreceptor outer segments. (c) 2007 Elsevier Ltd. All rights reserved.