最新一期美国《人类分子遗传学》杂志刊登的研究成果称,宾夕法尼亚大学医学院的研究人员成功培育出了一种转基因老鼠,可以用于研究老年人中常见的眼疾——老年性黄斑变性。这是科学家培育出的首个研究该病的动物模型。
黄斑变性是由于视网膜色素上皮和基底膜之间出现沉积物造成的。沉积物从初始形态开始慢慢演变成为细胞外的蛋白质和脂质堆积物,最终会导致患者失明。部分黄斑变性患者是由遗传所致,此前的研究已确定,人体内一个名为Efemp1的基因发生变异就会导致眼部出现黄斑变性。
宾夕法尼亚大学的研究小组把这种致病的变异基因成功引入实验鼠体内,结果"转基因鼠"的眼部也像人类患者一样,逐渐出现沉积物,患上了黄斑变性。
研究人员说,利用新培育出的这种转基因鼠,研究人员可跟踪黄斑变性的整个病程,这将是寻找黄斑变性有效疗法的重要一步,他们将来还可以在实验鼠身上测试一些新疗法。
黄斑变性是导致老年人失明的最常见病因。数据显示,目前仅美国就有超过1000万老年人患有黄斑变性。（新华社）
Drusen (extracellular deposits of protein and lipids that accumulate and can cause blindness) in macular degeneration. A. Drawing of eye showing location of macula at the center of the retina. B. Photograph of the macula from a patient with drusen. C. Histologic section of retina showing drusen between the retinal pigment epithelium (RPE) and Bruch's membrane. (Credit: Eric A. Pierce, MD, PhD; Ann Milam, PhD, University of Pennsylvania School of Medicine; National Eye Institute)
英语原文：http://www.sciencedaily.com/releases/2007/10/071009160225.htm
原始出处:
Human Molecular Genetics Advance Access originally published online on July 30, 2007
Human Molecular Genetics 2007 16(20):2411-2422; doi:10.1093/hmg/ddm198
The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice
Li Fu1, Donita Garland1, Zhenglin Yang2,3, Dhananjay Shukla4, Anand Rajendran4, Erik Pearson2,3, Edwin M. Stone5, Kang Zhang2,3 and Eric A. Pierce1,*
1 F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, 2 Department of Ophthalmology and Visual Sciences, 3 Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, UT, USA, 4 Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Madurai, Tamil Nadu, India and 5 Howard Hughes Medical Institute and Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
* To whom correspondence should be addressed at: F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, 305 Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA. Tel: +1 2155733919; Fax: +1 2155738030; Email: epierce@mail.med.upenn.edu
Received June 14, 2007; Accepted July 17, 2007
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.
