Formation and progression of sub-retinal pigment epithelium deposits in Efemp1 mutation knock-in mice:: a model for the early pathogenic course of macular degeneration
Formation and progression of sub-retinal pigment epithelium deposits in Efemp1 mutation knock-in mice:: a model for the early pathogenic course of macular degeneration
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DOI：
10.1093/hmg/ddm199
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发表时间：
2007-10-15
影响因子：
3.5
通讯作者：
Marmorstein, Alan D.
中科院分区：
文献类型：
--
作者：
Marmorstein, Lihua Y.;McLaughlin, Precious J.;Marmorstein, Alan D.
Malattia leventinese（ML）是一种显性遗传性黄斑变性疾病，其特征在于存在视网膜下色素上皮（RPE）沉积。除了发病年龄较早外，ML患者表现出与年龄相关性黄斑变性（AMD）诊断相符的症状和组织病理学，AMD是不可治愈的失明的最常见原因。ML是由编码fibulin-3（一种功能未知的蛋白质）的基因EFEMP 1中的突变（R345 W）引起的。我们产生了一个敲入小鼠携带疾病相关的突变在小鼠Efemp 1基因。小的，孤立的亚RPE存款早在4个月大的杂合和纯合基因敲入小鼠。随着时间的推移，这些沉积物的尺寸和数量增加，最终成为连续的薄片。在老年小鼠中，在沉积物内和布鲁赫膜内观察到膜碎片，并伴有一般RPE和脉络膜异常，包括RPE基底内折叠的变性、空泡化、丢失或破坏、脉络膜萎缩以及细胞突起局部增厚和侵入布鲁赫膜。发现Fibulin-3积聚在RPE下沉积物中。因此，Efemp 1基因敲入小鼠重建了ML和AMD最重要的组织病理学症状。我们的结论是，这些小鼠是一个有价值的工具，用于研究与黄斑变性相关的基础存款的主要致病过程，并为这类疾病的预防和治疗策略进行测试。
Malattia leventinese (ML) is a dominantly inherited macular degenerative disease characterized by the presence of sub-retinal pigment epithelium (RPE) deposits. With the exception of an earlier age of onset, ML patients exhibit symptoms and histopathology compatible with the diagnosis of age-related macular degeneration (AMD), the most common cause of incurable blindness. ML is caused by a mutation (R345W) in the gene EFEMP1 which encodes fibulin-3, a protein of unknown function. We generated a knock-in mouse carrying the disease-associated mutation in the murine Efemp1 gene. Small, isolated sub-RPE deposits developed as early as 4 months of age in both heterozygous and homozygous knock-in mice. Over time these deposits increased in size and number eventually becoming continuous sheets. In older mice membranous debris was observed within the deposits and within Bruch's membrane, and was accompanied by general RPE and choroidal abnormalities including degeneration, vacuolation, loss or disruption of the RPE basal infoldings, choroidal atrophy, and focal thickening of and invasion of cellular processes into Bruch's membrane. Fibulin-3 was found to accumulate in the sub-RPE deposits. Thus, the Efemp1 knockin mice reconstitute the most important histopathologic symptoms of both ML and AMD. We conclude that these mice are a valuable tool for studying the primary pathogenic course of basal deposits associated with macular degeneration and for testing prevention and treatment strategies for this class of diseases.