Human Molecular Genetics Advance Access published online on July 30, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm198
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The R345W Mutation in EFEMP1 is Pathogenic, and Causes AMD-Like Deposits in Mice
1 F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 2 Department of Ophthalmology and Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA 3 Program in Human Molecular Biology & Genetics, Eccles Institute of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah, USA 4 Aravind Eye Hospital & Postgraduate Institute of Ophthalmology, Madurai, Tamil Nadu, India 5 Howard Hughes Medical Institute and Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, Iowa
* Corresponding Author: Eric A. Pierce, M.D., Ph.D., F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, 305 Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, Phone: 215-573-3919, Fax: 215-573-8030, Email: epierce{at}mail.med.upenn.edu
Received June 14, 2007; Revised July 17, 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 (DHRD/ML) 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 that 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.
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