最新一期美國《人類分子遺傳學》雜志刊登的研究成果稱,賓夕法尼亞大學醫(yī)學院的研究人員成功培育出了一種轉基因老鼠,可以用于研究老年人中常見的眼疾——老年性黃斑變性,。這是科學家培育出的首個研究該病的動物模型,。
黃斑變性是由于視網膜色素上皮和基底膜之間出現沉積物造成的,。沉積物從初始形態(tài)開始慢慢演變成為細胞外的蛋白質和脂質堆積物,最終會導致患者失明。部分黃斑變性患者是由遺傳所致,此前的研究已確定,人體內一個名為Efemp1的基因發(fā)生變異就會導致眼部出現黃斑變性,。
賓夕法尼亞大學的研究小組把這種致病的變異基因成功引入實驗鼠體內,結果"轉基因鼠"的眼部也像人類患者一樣,逐漸出現沉積物,患上了黃斑變性。
研究人員說,利用新培育出的這種轉基因鼠,研究人員可跟蹤黃斑變性的整個病程,這將是尋找黃斑變性有效療法的重要一步,他們將來還可以在實驗鼠身上測試一些新療法,。
黃斑變性是導致老年人失明的最常見病因,。數據顯示,目前僅美國就有超過1000萬老年人患有黃斑變性。（新華社）
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)
英語原文：http://www.sciencedaily.com/releases/2007/10/071009160225.htm
原始出處:
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: [email protected]
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.
