Fu Li, Garland Donita, Yang Zhenglin, Shukla Dhananjay, Rajendran Anand, Pearson Erik, Stone Edwin M, Zhang Kang, Pierce Eric A
F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Hum Mol Genet. 2007 Oct 15;16(20):2411-22. doi: 10.1093/hmg/ddm198. Epub 2007 Jul 30.
Age-related macular degeneration (AMD) is the most common cause of vision loss in developed countries. A defining characteristic of this disorder is the accumulation of material between Bruch's membrane and the retinal pigment epithelium (RPE), first as microscopic basal deposits and later as clinically evident drusen. The pathogenesis of these deposits remains to be defined. Biochemical and genetic studies have suggested that inflammation and complement activation may play roles in AMD. Several lines of evidence also suggest that alterations to the extracellular matrix (ECM) of the RPE and choroid contribute to the development of AMD. The inherited macular degeneration Doyne honeycomb retinal dystrophy/Malattia Leventinese is thought to be caused by an R345W mutation in the EFEMP1 gene (also called fibulin-3). The pathogenicity of this mutation has been questioned because all individuals identified to date with the R345W mutation have shared a common haplotype. We investigated the pathogenicity of this mutation in families with early-onset macular degeneration and by generating Efemp1-R345W knockin mice. Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype. The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD. These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein. Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice. These results confirm that the R345W mutation in EFEMP1 is pathogenic. Further, they suggest that alterations in the ECM may stimulate complement activation, demonstrating a potential connection between these two etiologic factors in macular degeneration.
年龄相关性黄斑变性（AMD）是发达国家视力丧失的最常见原因。这种疾病的一个决定性特征是在布鲁赫膜和视网膜色素上皮（RPE）之间有物质积聚，最初是微观的基底沉积物，后来是临床上明显的玻璃膜疣。这些沉积物的发病机制尚待确定。生化和遗传学研究表明，炎症和补体激活可能在AMD中起作用。几条证据线索还表明，RPE和脉络膜的细胞外基质（ECM）改变促成了AMD的发展。遗传性黄斑变性多伊内蜂窝状视网膜营养不良/莱文蒂内斯病被认为是由EFEMP1基因（也称为纤维连接蛋白-3）中的R345W突变引起的。由于迄今鉴定出的所有携带R345W突变的个体都共享一个共同的单倍型，因此对该突变的致病性提出了质疑。我们通过对早发性黄斑变性家族进行研究并生成Efemp1-R345W基因敲入小鼠来调查该突变的致病性。遗传学研究表明，其中一个鉴定出的携带R345W突变的家族具有一种新的单倍型。突变的Efemp1-R345W小鼠在布鲁赫膜和RPE之间出现物质沉积，类似于AMD患者的基底沉积物。这些基底沉积物含有Efemp1和Timp3（一种与Efemp1相互作用的蛋白质）。在突变小鼠的RPE和布鲁赫膜中检测到补体激活的证据。这些结果证实EFEMP1中的R345W突变具有致病性。此外，它们表明ECM的改变可能刺激补体激活，证明了黄斑变性中这两个病因之间的潜在联系。
